USOO6325987B1 (12) United States Patent (10) Patent No.: US 6,325,987 B1 Sapieszko et al. (45) Date of Patent: Dec. 4, 2001
(54) MINERALS AND METHODS FOR THEIR Famery, R. et al., “Preparation of alpha-and beta-tricalcium PRODUCTION AND USE phosphate ceramics, with and without magnesium addition,” Ceram. Int., 1994, 20, 327–336. (75) Inventors: Ronald S. Sapieszko, Woodbury, MN (US); Erik M. Erbe, Berwyn, PA (US) Fukase, Y. et al., "Setting reactions and compressive Strengths of calcium phosphate cements,” J. Dent. Res., (73) Assignee: Vita Licensing, Inc., Wilmington, DE 1990, 69(12), 1852–1856. (US) Greenwood, N.N. et al., “Oxoacids of phosphorus and their (*) Notice: Subject to any disclaimer, the term of this salts.” Chemistry of the Elements, Pergamon Press, 1984, patent is extended or adjusted under 35 586-595. U.S.C. 154(b) by 0 days. Ishikawa, K. et al., “Properties and mechanisms of fast-Set ting calcium phosphate cements,” J. Mat. Sci. Mat. Med., (21) Appl. No.: 09/295,506 1995, 6,528-533. (22) Filed: Apr. 21, 1999 Koutsoukos, P. et al., “Crystallization of calcium phos Related U.S. Application Data phates. A constant composition Study, J. Am. Chem. Soc., 1980, 102, 1553–1557. (62) Division of application No. 08/784,439, filed on Jan. 16, 1997, now Pat. No. 5,939,039. Lacout, J.L., “Calcium phosphate as bioceramics,” in Bio materials-Hard Tissue Repair and Replacement, Elsevier (51) Int. Cl." - C01B 25/32 Science Publishers, 1992, 81–95. LeGeros, R.Z., "Biodegradation and bioresorption of cal (52) U.S. Cl...... 423/305; 423/311; 424/602 cium phospate ceramics.” Clin. Mat., 1993, 14(1), 65-88. (58) Field of Search ...... 423/305, 311, LeGeros, R.Z., "Preparation of octacalcium phosphate 423/314, 315; 424/602, 603 (OCP): A direct fast method.” Calcif. Tiss. Int., 1985, 37, 194-197. (56) References Cited Mirtchi, A. et al., “Calcium phosphate cements: Effect of U.S. PATENT DOCUMENTS fluorides on the Setting and hardening of beta-tricalcium 3,679,360 7/1972 Rubin et al...... 23/109 phosphate-dicalcium phosphate-calcite cements,” 4,149,893 4/1979 Aoki et al...... 106/35 Biomat., 1991, 12, 505-510. 4,612,053 9/1986 Brown et al...... 706/35 4,673,355 6/1987 Farris et al...... 433/218 Monma, H. et al., “Properties of hydroxyapatite prepared by 4,711,769 12/1987 Inoue et al...... 423/308 the hydrolysis of tricalcium phosphate,” J. Chem. Tech. 4,849, 193 7/1989 Palmer et al. . ... 423/308 Biotechnol., 1981, 31, 15-24. 4,880,610 11/1989 Constantz ...... 423/305 4,891,164 1/1990 Gaffney et al. ... 252/629 Nancollas, G.H., “The involvement of calcium phosphates 4,897.250 1/1990 Sumita ...... 423/308 in biological mineralization and demineralization pro 5,034,352 7/1991 Vit et al...... 501/1 cesses.” Pure Appl. Chem., 1992, 64(11), 1673–1678. 5,047,031 9/1991 Constantz ...... 606/77 5,053,212 * 10/1991 Constantz et al. . ... 423/305 5,129,905 7/1992 Constantz ...... 606/76 (List continued on next page.) 5,302,362 4/1994 Bedard ...... 423/306 5,322,675 6/1994 Hakamatsuka et al...... 423/311 5,338,334 8/1994 Zhen et al...... 75/362 Primary Examiner Stuart L. Hendrickson 5,409,982 4/1995 Imura et al...... 524/417 (74) Attorney, Agent, or Firm Woodcock Washburn LLP 5,427,754 6/1995 Nagata et al. . ... 423/308 5,496.399 3/1996 Ison et al...... 106/35 (57) ABSTRACT 5,522,893 6/1996 Chow et al...... 623/11 Uniformly sized and shaped particles of metal Salts are 5,525,148 6/1996 Chow et al...... 106/35 provided comprised of one or more metal cations in com 5,545,254 8/1996 Chow et al...... 106/35 bination with one or more simple oxoacid anions and a OTHER PUBLICATIONS general method for the controlled precipitation of Said metal Abbona, F. et al., “Crystallization of calcium and magne Salts from aqueous Solutions. The methods proceed via the sium phosphates from Solutions of medium and low con in Situ homogeneous production of simple or complex centrations.” Cryst. Res. Technol., 1992, 27, 41-48. OXoacid anions in which one or more of the nonmetallic Brown, P.W. et al., “Variations in solution chemistry during elements e.g. Group 5B and 6B (chalcogenides), and 7B the low temperature formation of hydroxyapaptite,” J. Am. (halides) comprising the first oxoacid anion undergo oxida Ceram. Soc., 1991, 74(8), 1848–1854. tion to generate the precipitant anionic Species along with Chaair, H. et al., “Precipitation of stoichiometric apatitic concurrent reduction of the nonmetallic element of a Second, tricalcium phosphate prepared by a continuous process,” J. dissimilar oxoacid anion. The oxoacid anions are initially Mater. Chem., 1995, 5(6), 895–899. present in Solution with one or more metal cations known to Driessens, F.C.M. et al., “Effective formulations for the form insoluble Salts with the precipitant anion. preparation of calcium phosphate bone cements,” J. Mat. Sci. Mat. Med., 1994, 5, 164-170. 12 Claims, 22 Drawing Sheets US 6,325,987 B1 Page 2
OTHER PUBLICATIONS Vereecke G. et al., “Calculation of the solubility diagrams in the system Ca(OH)-HPO, KOH-HNO-CO Nancollas, G.H., “In vitro studies of calcium phosphate H.O.” J. Cryst. Growth, 1990, 104, 820–832. crystallization,” in Biomineralization Chemical and Bio Wong, A.T.C. et al., “Prediction of precipitation and trans chemical Perspectives, 1989, 157-187. formation behavior of calcium phosphate in aqueous Nancollas, G.H. et al., “Formation and dissolution mecha nisms of calcium phosphates in aqueuos Systems,” in media,” in Hydroxyapatite and Related Materials, Brown, Hydroxyapatite and Related Materials, CRC Press, Inc. P.W. et al. (eds.) CRC Press, Inc., 1994, 189-196. 1994, 73–81. * cited by examiner U.S. Patent Dec. 4, 2001 Sheet 1 of 22 US 6,325,987 B1
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s OOOd AISueu O US 6,325,987 B1 1 2 MINERALS AND METHODS FOR THEIR alizers and cements; U.S. Pat. No. 4,673,355 E. T. Farris, PRODUCTION AND USE et al., “Solid calcium phosphate materials;” U.S. Pat. No. 4,849,193, J. W. Palmer, et al., “Process of preparing CROSS-REFERENCE TO RELATED hydroxyapatite;” U.S. Pat. No. 4,897.250, M. Sumita, “Pro APPLICATION cess for producing calcium phosphate,” U.S. Pat. No. 5,322, 675, Y. Hakamatsuka, “Method of preparing calcium phos This application is a division of Applicant's application phate;” U.S. Pat. No. 5,338,356, M. Hirano, et al “Calcium Ser. No. 08/784,439, filed Jan. 16, 1997, now U.S. Pat. No. phosphate granular cement and method for producing 5,939,039. 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 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 15 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 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 25 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 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 35 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. 40 improved uniformity, biological activity, and other proper Different Stoichiometric compositions Such as hydroxyapa ties. tite (HAp), tricalcium phosphate (TCP), and tetracalcium 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 45 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 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 Further objects will become apparent from a review of the from chemical and processing shortcomings that limited 50 Stoichiometric control, crystal morphology, Surface present specification. properties, and, ultimately, reactivity in the body. Intensive milling and comminution of natural minerals of varying SUMMARY OF THE INVENTION 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 55 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 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, 60 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 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. 65 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 method Starts from raw materials, which are described US 6,325,987 B1 3 4 herein as Salts, aqueous Solutions of Salts, stable hydroSols or f-tricalcium phosphate (B-TCP) major phase-apatite (Cas other Stable dispersions, and/or inorganic acids. The phases (PO)(OH)) minor phase). The spectrum shows a signifi produced by the methods of this invention Redox Precipi cant difference in the intensity of the HAppeaks, as com tation Reaction (RPR) and HYdrothermal PRocessing pared to that in FIG. 7. (HYPR) are generally intermediate precursor minerals in FIG. 9 depicts Fourier Transform Infrared (FTIR) spectra the physical form of powders, particulates, Slurries, and/or of calcium phosphate as used for FIG. 8, indicating the pastes. These precursor minerals can be easily converted to presence of CO. vibrations, at 880, 1400, and 1450 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 15 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 BRIEF DESCRIPTION OF THE DRAWINGS (PO). FIG. 12 is an X-ray Diffraction (XRD) plot of RPR FIG. 1 depicts an aggregated physical Structure of an RPR 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) ?-Ca(PO4)2+Cas 25 indicate the presence of the crystal phase AlPO. (PO) (CO)(OH) prepared in accordance with one FIG. 13 is an X-ray Diffraction (XRD) plot of HYPR embodiment this invention. The entire agglomerated particle generated calcium phosphate precursor mineral heated to is 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 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 35 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. 40 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 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 45 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 (PO) (CO)(OH) crystallites. indicate the presence of the crystal phases 3-tricalcium FIG. 17A is an X-ray Diffraction (XRD) plot of RPR and phosphate (B-TCP) major phase-calcium pyrophosphate 50 HYPR generated calcium phosphate precursor minerals, (CaFIPO7) 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 monetite, CaHPO, mixed with B-TCP+type-B, carbonated 500 C. for 1 hour. The peak position and relative intensities apatite (c-HAp) B-Ca(PO)2+Cas(PO) (CO)(OH) indicate the presence of the crystal phases 3-tricalcium 55 crystallites. phosphate (B-TCP) major phase+apatite (Cas(PO)(OH)) FIG. 17B is an X-ray Diffraction (XRD) plot of RPR and minor phase. 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 60 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 crystal phases f-tricalcium phosphate (B-TCP) major lites. 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 65 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 mium phosphate hydrate NdPO-0.5H2O). US 6,325,987 B1 S 6 FIG. 18B is an X-ray Diffraction (XRD) plot of RPR duced as hypophosphorus acid or a Soluble alkali or generated neodymium phosphate precursor mineral heated alkaline-earth hypophosphite Salt. For the preparation of to 700° C. for 1 hour. The peak position and relative Such calcium phosphates, it is preferred that the initial pH be intensities indicate the presence of the crystal phase maintained below about 3, and still more preferably below Monazite-Nd NdPO). about 1. FIG. 18C is an X-ray Diffraction (XRD) plot of RPR The intermediate precursor minerals prepared in accor generated cerium phosphate precursor mineral heated to dance with the present methods are, themselves, novel and 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 indicate the presence of the crystal phase Xenotime YPO). heated, or otherwise treated, to change their properties. 15 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 In accordance with the present invention, methods are neous materials from the mineral precursor, will alter its provided for preparing an intermediate precursor mineral of composition and morphology in Some cases, and can confer at least one metal cation and at least one oxoanion. These upon the mineral a particularized and preselected crystalline methods comprise preparing an aqueous Solution of the Structure. Such heat treatment is to temperatures which are metal cation and at least one oxidizing agent. The Solution considerably less than are conventionally used in accordance is augmented with at least one Soluble precursor anion with prior methodologies used to produce the end product oxidizable by Said oxidizing agent to give rise to the mineral phases. Accordingly, the heat treatments of the precipitant OXoanion. The oxidation-reduction reaction thus 25 present invention do not, of necessity, give rise to the contemplated is conventionally initiated by heating the common crystalline morphologies Structures of monetite, Solution under conditions of temperature and pressure effec dicalcium or tricalcium phosphate, tetracalcium phosphate, tive to give rise to Said initiation. In accordance with etc., but, rather, to new and unobvious morphologies which preferred embodiments of the invention, the oxidation have great utility in the practice of the present invention. 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, precipitate from the Solution. medical, and other fields. Thus, calcium phosphate minerals The intermediate precursor mineral thus prepared can be produced in accordance with preferred embodiments of the treated in a number of ways. Thus, it may be heat treated in present invention may be used in dental and orthopaedic accordance with one or more paradigms to give rise to a 35 Surgery for the restoration of bone, tooth material and the preSelected crystal Structure or other preselected morpho like. The present minerals may also be used as precursors in logical Structures therein. chemical and ceramic processing, and in a number of In accordance with preferred embodiments, the oxidizing industrial methodologies, Such as crystal growth, ceramic agent is nitrate ion and the gaseous product is a nitrogen processing, glass making, catalysis, bioseparations, pharma oxide, generically depicted as NO. It is preferred that the 40 ceutical excipients, gem Synthesis, and a host of other uses. precursor mineral provided by the present methods be Uniform microStructures of unique compositions of miner Substantially homogeneous. It is also preferred that the als produced in accordance with the present invention confer temperature reached by the oxidation-reduction reaction not upon Such minerals wide utility and great “value added.” exceed about 150 C. unless the reaction is run under 45 Improved precursors provided by this invention yield hydrothermal conditions or in a pressure vessel. lower temperatures of formation, accelerated phase transi In accordance with other preferred embodiments, the tion kinetics, greater compositional control, homogeneity, intermediate precursor mineral provided by the present and flexibility when used in chemical and ceramic pro invention is a calcium phosphate. It is preferred that Such cesses. Additionally, these chemically-derived, ceramic pre mineral precursor comprise, in major proportion, a Solid 50 cursors have fine crystal size and uniform morphology with phase which cannot be identified Singularly with any con Subsequent potential for more closely resembling or mim ventional crystalline form of calcium phosphate. At the same icking natural Structures found in the body. time, the calcium phosphate mineral precursors of the Controlled precipitation of Specific phases from aqueous present invention are Substantially homogeneous and do not Solutions containing metal cations and phosphate anions comprise a physical admixture of naturally occurring or 55 represents a difficult technical challenge. For Systems con conventional crystal phases. taining calcium and phosphate ions, the situation is further In accordance with preferred embodiments, the low tem complicated by the multiplicity of phases that may be perature processes of the invention lead to the homogeneous involved in the crystallization reactions as well as by the precipitation of high purity powders from highly concen facile phase transformations that may proceed during min trated Solutions. Subsequent modest heat treatments convert 60 eralization. The Solution chemistry in aqueous Systems con the intermediate material to e.g. novel monophasic calcium taining calcium and phosphate Species has been Scrupu phosphate minerals or novel biphasic B-tricalcium phoS lously investigated as a function of pH, temperature, phate (B-TCP)+type-B, carbonated apatite (c-HAp) B-Ca concentration, anion character, precipitation rate, digestion (PO)+Cas(PO) (CO)(OH) particulates. time, etc. (P. Koutsoukos, Z. Amjad, M. B. Tomson, and G. In other preferred embodiments, calcium phosphate Salts 65 H. Nancollas, “Crystallization of calcium phosphates. A are provided through methods where at least one of the constant composition study,” J. Am. Chem. Soc. 102: 1553 precursor anions is a phosphorus Oxoanion, preferably intro (1980); A. T. C. Wong. and J. T. Czernuszka, “Prediction of US 6,325,987 B1 7 8 precipitation and transformation behavior of calcium phoS beta-tricalcium phosphate ceramics, with and without mag phate in aqueous media, in Hydroxyapatite and Related nesium addition.” Ceram. Int. 20:327 (1994); Y. Fukase, E. Materials, pp 189-196 (1994), CRC Press, Inc.; G. H. D. Eanes, S. Takagi, L. C. Chow, and W. E. Brown, “Setting Nancollas, “In vitro studies of calcium phosphate reactions and compressive Strengths of calcium phosphate crystallization,” in Biomineralization-Chemical and Bio cements,” J. Dent. Res.69(12): 1852 (1990). chemical Perspectives, pp 157-187 (1989)). The present invention represents a significant departure Solubility product considerations impose Severe limita from prior methods for Synthesizing metal phosphate min tions on the solution chemistry. Furthermore, methods for erals in general, and calcium phosphate powders in 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 invention, has been found to be a means of producing Several sparingly Soluble calcium phosphate crystalline 15 particulates of uniform Size and composition in a form phases, So called “basic calcium phosphates, have been heretofore not observed in the prior art. characterized, including alpha- and beta-tricalcium phos The use of hypophosphite H2PO anion as a precursor phate (C-TCP, B-TCP, Ca(PO)), tetracalcium phosphate to phosphate ion generation has been found to be preferred (TTCPCa(PO).O), octacalcium phosphate (OCP, Cal H Since it circumvents many of the Solubility constraints (PO).-nH2O, where 2
Heated to 500° C., 1 h (Major) Whitlockite B-Cas(PO), Considerable amounts of NO, were evolved during firing (minor) Cas (PO4)3(CO)(OH) of the samples at or above 300° C. 60 Example 2 Comparing the XRD spectra in FIG. 7 and 8 shows the Novel Low Temperature Calcium Phosphate difference in the amount of HAp-Cas(PO) (CO)(OH) Powder Preparation phase present for each minor phase from Example 1 (which 65 had no acetate) and Example 3 (acetate present), respec Example 1 was repeated using five times the indicated tively. This is indicative of the counteranion effect on crystal weights of reagents. The reactants were contained in a 5/2" formation. US 6,325,987 B1 15 Fourier Transform Infrared (FTIR) spectra were obtained using a Nicolet instrument (model number 5DXC) run in the diffuse reflectance mode over the range of 400 to 4000 cm. Heated to 500° C., 1 h (Major) Whitlockite B-Cas(PO), The presence of the carbonated form of HAp is confirmed by (minor) CaPO, the FTIR spectra in FIG. 9 (400 to 1600 cm), which indicates the presence of peaks characteristic of IPO (580–600, 950–1250 cm) and of CO, (880, 1400, & Example 6 1450 cm). The P=O stretch, indicated by the strong peak Novel Low Temperature Zinc Phosphate Powder at 1150–1250 cm, suggests a structural perturbation of Preparation hydroxyapatite by the carbonate ion. An aqueous solution of 8.51 g 50 wt % HPO in 8.00 g Example 4 distilled water was prepared as described in Example 1. To this Solution was added 28.78 g Zinc nitrate hexahydrate Salt, 15 Zn(NO).6H2O (ACS reagent, Aldrich Chemical Co., Inc. Colloidal SiO, added to calcium phosphate #22,873-7, CAS #10196-18-6), equivalent to 21.97 wt % mixtures via RPR Zn. The molar ratio of Zn/phosphate in this mixture was 3/2 and the equivalent solids level as Zn(PO) was 27.5 wt An aliquot of 8.00 g 34.0 wt % SiO hydrosol (Nalco %. Endothermic dissolution of the zinc nitrate hexahydrate Chemical Co., Inc. #1034A, batch #B5G453C) was slowly proceeded giving a homogeneous Solution once the Sample added to 8.51 g 50 wt % aqueous solution of HPO with warmed to room temperature. Further warming of this rapid Stirring to give a homogeneous, weakly turbid colloi solution to >25 C. on a hotplate initiated a reaction in which dal dispersion. To this dispersion was added 22.85 g the solution vigorously evolved red-brown acrid fumes of Ca(NO).4H2O salt such that the molar ratio of calcium/ NO. The reaction continued for approximately 10 min phosphate in the mixture was 3/2. Endothermic dissolution 25 utes while the sample remained a clear, colorleSS Solution, of the calcium nitrate tetrahydrate proceeded giving a homo abated Somewhat for a period of five minutes, then Vigor geneous colloidal dispersion once the Sample warmed to ously resumed finally resulting in the formation of a mass of moist white solid, some of which was very adherent to the room temperature. The colloidal SiO was not flocculated walls of the Pyrex beaker used as a reaction vessel. The hot despite the high acidity and ionic strength in the sample. Solid was allowed to cool to room temperature and was Warming of the sample on a hotplate to >25 C. initiated a Stored in 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 ment in air at 500 C. for 1 hour, XRD indicated the solid conducted as described in Example 1. Following heat treat 35 to be composed of Zn(PO) (see FIG. 10). ment in air at 500 C. for 1.0 hour, XRD indicated the solid to be composed of whitlockite plus hydroxyapatite. Heated to 500° C., 1 h (Major) Zn(PO4)2 40 Heated to 300° C., 2 h (Major) Calium pyrophosphate Ca2PO, (minor) Octacalcium phosphate Example 7 CaH(PO).2H2O Heated to 500° C., 1 h (Major) Whitlockite B-Cas(PO), Novel Low Temperature Iron Phosphate Powder HAp Cas(PO4)(OH) Preparation (minor) 45 An aqueous solution of 17.50 g 50 wt % HPO was combined with 15.00 g distilled water to form a clear, Example 5 colorless solution contained in a 250 ml Pyrex beaker on a hotplate/stirrer. To this solution was added 53.59 g ferric Novel Low Temperature Calcium Phosphate 50 nitrate nonahydrate salt, Fe(NO)-9H2O (ACS reagent, Powder Preparation Alfa/Aesar reagent #33315, CAS #7782-61-8), equivalent to 13.82 wt % Fe. The molar ratio of Fe/phosphate in this Example 1 was repeated with the addition of 10.00 g mixture was 1/1 and the equivalent solids level as FePO dicalcium phosphate dihydrate, DCPD, CaHPO4.2H2O was 23.2 wt %. Endothermic dissolution of the ferric nitrate 55 nonahydrate Salt proceeded partially with gradual warming (Aldrich Chemical Co., Inc. #30,765-3, CAS #7789-77-7) to of the reaction mixture, eventually forming a pale lavender the homogeneous Solution following endothermic dissolu Solution plus undissolved salt. At Some temperature >25 C., tion of the calcium nitrate salt. The DCPD was present both an exothermic reaction was initiated which evolved NO. as Suspended Solids and as precipitated material (no agita This reaction continued for approximately 15 minutes dur tion used). Warming of the sample to >25 C. initiated an 60 ing which time the reaction mixture became Syrup-like in exothermic reaction as described in Example 1, resulting in Viscosity. With continued reaction, Some pale yellow Solid the formation of a white, pasty Solid. Heat treatment and began to form at the bottom of the beaker. After approxi X-ray diffraction of this solid were conducted as described mately 40 minutes of reaction, the Sample was allowed to in Example 1. Following heat treatment in air at 500 C. for cool to room temperature. The product consisted of an 1 hour, XRD indicated the solid to be composed of whit 65 inhomogeneous mixture of low density yellow Solid at the lockite as the primary phase along with calcium pyrophoS top of the beaker, a brown liquid with the consistency of phate (Ca2PO7) as the Secondary phase. caramel at the center of the product mass, and a Sand colored US 6,325,987 B1 17 18 Solid at the bottom of the beaker. The Solids were collected exotherm. The product was cooled in air to a white crumbly as Separate Samples insofar as was possible. Solid which was Stored in a polyethylene Vial. Heat treatment and X-ray diffraction of the solid collected Heat treatment and X-ray diffraction of this solid were from the top of the beaker were conducted as described in conducted as described in Example 1. Following heat treat Example 1. Following heat treatment in air at 500 C. for 1 ment in air at 500 C. for either 0.5 or 1 hour, XRD indicated hour, XRD indicated the solid to be composed of graftonite the Solid to be composed of whitlockite as the primary phase Fe(PO) plus Some amorphous material, Suggesting that along with hydroxyapatite as the Secondary phase. XRD the heat treatment was not Sufficient to induce complete results indicate that the relative ratio of the two calcium sample crystallization (see FIG. 11). phosphate phases was dependent on the duration of the heat treatment, but no attempts were made to quantify the depen dence. Heated to 500° C., 1 h (Major) Graftonite Fe(PO).
Some mechanism apparently occurs by which Fe" was 15 Heated to 500° C., 1 h (Major) Whitlockite B-Cas(PO), reduced to Fe’". (minor) Cas (PO4)3(CO)(OH) Example 8 Example 10 Novel Low Temperature Calcium Phosphate 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, An aqueous solution of 10.82 g 50 wt % HPO was colorless solution contained in a 250 ml Pyrex beaker. To combined with 2.00 g distilled water to form a clear, this solution was added 34.72g Ca(NO).4H2O. The molar 25 colorless Solution contained in a 250 ml beaker. To this ratio of Ca/phosphate in this mixture was 1/1 and the solution was added 30.78 g aluminum nitrate nonahydrate equivalent solids level as CaHPO was 33.8 wt %. Endot Salt, Al(NO).9H2O (ACS reagent, Alfa/Aesar reagent hermic dissolution of the calcium nitrate tetrahydrate pro #36291, CAS #7784-27-2), equivalent to 7.19 wt % Al. The ceeded under ambient temperature conditions, eventually molar ratio of Al/phosphate in this mixture was 1/1 and the forming a homogeneous Solution once the Sample warmed to equivalent solids level as AlPO was 22.9 wt %. Endot room temperature. Warming of this solution above 25 C. hermic dissolution of the aluminum nitrate nonahydrate initiated a vigorous exothermic reaction which resulted in proceeded giving a homogeneous Solution once the Sample the evolution of NO, rapid temperature increase of the warmed to room temperature. Further warming of this sample to >100° C., and extensive foaming of the reaction solution to >25 C. on a hotplate initiated a reaction in which mixture over the beaker rim, presumably due to flash boiling 35 the solution vigorously evolved red-brown acrid fumes of of water at the high reaction temperature. After cooling to NO, Reaction continued for approximately 15 minutes room temperature, the reaction product was collected as a during which the Solution Viscosity increased considerably dry, white foam which was consolidated by crushing to a prior to formation of a white solid. powder. Heat treatment and X-ray diffraction of this solid were Heat treatment and X-ray diffraction of this solid were 40 conducted as described in Example 1. Following heat treat conducted as described in Example 1. Results are as follows: ment in air at 500 C. for 0.5 hour, XRD indicated the solid to be composed of AlPO plus Some amorphous material, Suggesting that the heat treatment was not Sufficient to induce complete Sample crystallization (see FIG. 12). Heated to 300° C., 2 h (Major) CaPO, 45 (minor) Octacalcium phosphate CaH(PO)-2H2O Example 11 Heated to 500° C., 1 h (Major) CaPO, Novel Low Temperature Calcium Phosphate Powder Preparation 50 Example 9 An aqueous solution of 8.06 g 50 wt % HPO reagent was combined with 6.00 g distilled water to form a clear, Novel Low Temperature Calcium Phosphate colorless solution in a 250 ml Pyrex beaker on a hotplate/ Powder Preparation stirrer. To this solution was added 19.23g Ca(NO).4H2O. Example 3 was repeated using ten times the indicated 55 The molar ratio of Ca/phosphate in this sample was 4/3 and weights of reagents. The reactants were contained in a 5/2" the equivalent Solids as octacalcium phosphate, Cash diameter Pyrex crystallizing dish on a hotplate/stirrer. The (PO)-5H2O) was 30.0 wt %. Endothermic dissolution of reactants were Stirred continuously during the dissolution the calcium nitrate tetrahydrate proceeded under ambient and reaction Stages. The chemical reaction initiated by conditions, eventually forming a homogeneous Solution heating the solution to >25 C. resulted in the evolution of 60 once the Sample warmed to room temperature. Warming of NO, for several minutes with no apparent effect on the the solution above 25 C. initiated a vigorous exothermic Stability of the System, i.e. the Solution remained clear and reaction as described in Example 1. After approximately colorless with no evidence of Solid formation. After abating three minutes, the reaction was essentially complete leaving for Several minutes, the reaction resumed with increased a moist, white, pasty Solid. intensity resulting in the voluminous generation of NO, 65 Heat treatment and X-ray diffraction of this solid were and the rapid appearance of a pasty white Solid material. The conducted as described in Example 1. Following heat treat reaction vessel and product were both hot from the reaction ment in air at 500 C. for 0.5 hour, XRD indicated the solid US 6,325,987 B1 19 20 to be composed of whitlockite as the primary phase along immersed in the reactant Solutions and no corrosion was with hydroxyapatite as the Secondary phase. There was no observed. In addition, it is assumed that the high nitrate ion evidence for the formation of octacalcium phosphate (OCP), concentration in the reactant mixture provided a passivating despite the initial Sample Stoichiometry. This result Suggests environment for the type 316SS. that (a) alternate heat treatments are necessary to crystallize 5 One hundred grams (approximately 100 ml) of the cal OCP and/or (b) excess Ca is present in the intermediate cium nitrate-Sodium hypophosphite Solution was placed in powder. the Pyrex liner of the reactor and the intervening Space between the glass liner and the reactor vessel was filled with distilled water to the level of the sample. This ensured maximum heat transfer to the Sample Since the reactor was Heated to 500° C., 0.5 h (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 15 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 follows: Example 11 was repeated except that no distilled water was used in preparation of the reaction mixture. Warming of the homogeneous Solution above 25 C. initiated an exo thermic reaction as described in Example 11. After approxi REACTOR THERMAL PROFILE mately three minutes, the reaction was essentially complete Time(min) O 5 1O 15 2O 25 3O 35 36 leaving a moist, pasty, white Solid. Temp. 22 49 103 122 145 155 179 197 260 Heat treatment and X-ray diffraction of this solid were 25 ( C.) (hold) (+/-2 C.) conducted as described in Example 1. Following heat treat Pressure 16O 210 22O ment in air at 500 C. for 0.5 hour, XRD indicated the solid (psi) to be composed of calcium pyrophosphate (CalPO). After holding at 200+/-3 C. for 12 minutes, the temperature rapidly increased to 216 C. with a resultant increase in Heated to 500° C., 0.5 h (Major) CaPO, reactor preSSure to approximately 330 psi. This exothermic event quickly Subsided as evidenced by the rapid drop in reactor temperature to 208 C. within two minutes as the Example 13 35 Parr reactor approached thermal equilibrium via a near adiabatic process. After 15 minutes at 200 C., the reactor Novel Low Temperature Hydrothermal (HYPR) was removed from the heating mantle, quenched in a cold Calcium Phosphate Powder Preparation water bath, and opened after the head Space was vented to An aqueous solution of 50 wt % calcium nitrate ambient pressure. tetrahydrate, Ca(NO)-4H2O (ACS reagent, Aldrich 40 A white precipitate was present in the glass liner. The Chemical Co., Inc. #23,712-4, CAS #13477-34-4) was pre solid was collected by vacuum filtration on a 0.45 micron pared by dissolving 250.0 g of the salt in 250.0 g distilled membrane filter (Millipore, Inc., Bedford, Mass., 01730), water. This solution was equivalent to 8.49 wt % Ca. A total washed several times with distilled water, and dried at of 47.0 g of this Solution was added, with rapid agitation, to approximately 55 C. in a forced convection oven. X-ray an aqueous Solution of 50 wt % Sodium hypophosphite 45 diffraction of this solid was conducted as described in monohydrate, NaH2PO-H2O (Alfa/Aesar reagent Example 1. #14104, CAS #10039-56-2) also prepared by dissolving X-Ray diffraction results indicate a unique, unidentifiable 250.0 g of the salt in 250.0 g distilled water. The sodium diffraction pattern, see FIG. 13. hypophosphite solution was equivalent to 44.80 wt % Example 14 PO. The clear, colorless solution of calcium nitrate and 50 Sodium hypophosphite was then diluted with 40.3 g distilled Novel Low Temperature Hydrothermal (HYPR) water. The molar ratio of Ca/phosphate in this mixture was Calcium Phosphate Powder Preparation 5/3, and the equivalent solids level as Cas(PO)(OH) Example 13 was repeated except that 40.3 g of 1.0 M (hydroxyapatite) was 10.0 wt %. The sample was hydro NaOH solution was added with rapid stirring to the homo thermally treated using a 300 cc Volume Stirred high pres 55 geneous Solution of calcium nitrate and Sodium hypophos sure bench reactor (Model no. 4561 Mini Reactor, Parr phite instead of the distilled water. This base addition Instrument Co., Moline, Ill. 61265) equipped with a tem resulted in the formation of a milk white dispersion, pre perature controller/digital tachometer unit (Model no. 4842, sumably due to precipitation of Ca(OH). Parr Instrument Co.) and dial pressure gauge. All wetted The Sample was hydrothermally processed as described in parts of the reactor were fabricated from type 316 stainless 60 Example 13 with the temperature setpoint at 207 C. The steel. Ordinarily, type 316SS is not the material of choice for temperature ramp to 160° C. (25 minutes) was as indicated inorganic acid Systems Such as the Solution precursors used for Example 13. At 30 minutes into the run, an exotherm in this invention, Since phosphoric acid can attack StainleSS occurred causing the temperature of the reaction mixture to Steel at elevated temperatures and preSSures. However, in the rise to a maximum of 221 C. within five minutes with a practice of this invention, direct contact (i.e. wetting) of the 65 corresponding preSSure increase to 370 psi. At 38 minutes reactor Surfaces was avoided through the use of a Pyrex into the experiment, the reactor was quenched to room glass liner. Only the Stirrer and thermocouple sheath were temperature. US 6,325,987 B1 21 22 The reaction product consisted of a Small amount of white Example 16 precipitate. The material was collected as described in Example 13. X-ray diffraction of the dried sample was Novel Cement Composition conducted as described in Example 1. XRD results indicated the Solid to be comprised of the same unidentifiable pattern Approximately 1.4 g of an alkaline Solution (7 molar) (crystal phase) found in Example 13 and minor amounts of formed using NaOH and distilled water, was mixed with 1.1 HAp-Cas(PO)(OH)). (see FIG. 14). g of HYPR monetite Example 15 and 1.1 g of RPR Example 15 f8-TCP-HAp(CO) Example 3 in a glass mortar and pestle for ~45 Seconds. After mixing, a Smooth paste was formed, Novel Low Temperature Hydrothermal (HYPR) which was Scooped into a 3 ml polypropylene Syringe and Calcium Phosphate Powder Preparation sealed for 20 minutes without being disturbed. Room tem A total of 47.0 g of a 50 wt % aqueous solution of calcium perature Setting was observed after 20 minutes, which was nitrate tetrahydrate was diluted with 53.0 g distilled water. indicated by the use of a 454 gram Gilmore needle. The Then, 6.00 g calcium hypophosphite salt, Ca(HPO) (Alfa/ 15 hardened cement was analyzed by X-ray diffraction which Aesar reagent #56168, CAS #7789-79–9), equivalent to revealed a conversion to primarily type-B, carbonated apa 23.57 wt % Ca and 111.7 wt % PO, was slurried into the tite which is the desired bone mineral precursor phase (see Ca(NO) Solution using rapid agitation. An unknown FIG. 16): amount of the calcium hypophosphite remained undissolved in the room temperature sample. The solubility behavior of Ca(HPO) in the Ca(NO) solution at elevated tempera tures is unknown. The molar ratio of Ca/phosphate in this Cement XRD revealed (Major) Cas (PO4)3(CO)(OH) system was 1.91. (minor) Whitlockite B-Cas(PO), This Sample was hydrothermally processed as described in Example 13 with the temperature setpoint at 212 C. The 25 temperature ramp to 200 C. was as indicated for Example Example 17 13. At 39 minutes into the run, an exotherm occurred causing the temperature of the reaction mixture to rise to a maximum Novel Cement Composition of 252 C. within three minutes with a corresponding preSSure increase to 640 psi. At 44 minutes into the A stock solution was formed with the approximately 7 M experiment, the reactor was quenched to room temperature. NaOH solution used in Example 1 and 1.0% polyacrylic acid The reaction product appeared as a voluminous white (PAA). PAA is used as a chelating setting additive and precipitate plus Some Suspended Solids. The material was wetting agent. The above Solution was used with Several collected as described in Example 13. X-ray diffraction of 35 the dried Solid was conducted as described in Example 1. powder combinations to form setting cements. A 50/50 XRD indicated the solid to be monetite, CaHPO, see FIG. powder mix of HYPR monetite Example 15 and RPR 15. The unique crystal morphology is depicted in the Scan f8-TCP-HAp(CO) Example 3), approximately 0.7g, was ning electron micrograph representation in FIG. 2. mixed with a glass spatula on a glass plate with 0.39 g of the Mixtures of the above described RPR and HYPR powders 40 1% PAA-NaOH solution (powder to liquid ratio=1.73). The are useful in the formation of Self-setting calcium phosphate cement was extruded through a 3 ml Syringe and was Set cements for the repair of dental and Orthopaedic defects. The after being left undisturbed for 20 minutes at room tempera addition of Specific components and Solubilizing liquids can ture (23° C). also be added to form the precursor bone mineral constructs of this invention. Examples 18-34
Powderf Set Time (min.) Powderf Gilmore Needle Liquid ratio (454 grams) Example Powder Liquid (Consistency) # = (1200 grams)
18 HYPR monetite + 7M NaOH 1/1f1.2 <20 min RPR (Ex. 1) 500° C. Alkaline (slightly wet (#) Soln paste) 19 HYPR monetite 7M NaOH 1/1f1.2 <20 min (Ex. 15) + Alkaline (wet paste) (#) RPR (Ex. 1) 700° C. Soln 2O HYPR monetite 7M NaOH 1/1f1 15-18 min (Ex. 15) + Alkaline (sl. wet paste) -50 um 45S5" glass Soln 21 RPR (Ex. 1) 500° C. 7M NaOH 1.5/1 >40 min neat Alkaline (wet paste) Soln 22 RPR (Ex.1) 300° C. 7M NaOH 1.7/1 40 min -- Alkaline (sl. wet paste) RPR (Ex. 9) 500° C. Soln US 6,325,987 B1 23 24
-continued Powderf Set Time (min.) Powderf Gilmore Needle Liquid ratio (454 grams) Example Powder Liquid (Consistency) # = (1200 grams) 23 HYPR monetite 7M NaOH f1f1.4 No Set up to (Ex. 15) + Alkaline (v. gritty, wet) 24 hrs. Commercial B-TCP Soln 24 HYPR monetite 7M NaOH f1f1.4 20 min (Ex. 15) + Alkaline (slightly wet (#) RPR (Ex. 2) 500° C. Soln paste) 25 HYPR monetite 7M NaOH 1/1f1 <30 min (Ex. 15) + Alk. Soln + (claylike sl. set RPR (Ex. 2) 500° C. 20% PAA paste) 26 HYPR monetite 7M NaOH 1/1f1 35 min. (Ex. 15) + Alk. Soln + (claylike RPR (Ex. 2) 500° C. 5% PAA paste) 27 HYPR monetite 7M NaOH f1f1.2 12-15 min (Ex. 15) + Alk. Soln + (slightly dry RPR (Ex. 11) 500° C. % PAA paste) 28 HYPR monetite O wt % f1f1.2 1 hr 15 min (Ex. 15) + Ca(HPO), (very wet RPR (Ex. 1) 500° C. (aq) paste) 29 RPR (Ex. 11) 500° C. O wt % 1.7/1 45 min neat Ca(H2PO). (very wet (aq) paste) 3O RPR (Ex. 11) 500° C. O wt % 2.5/1 20 min neat Ca(H2PO). (sl. dry (aq) paste? putty) 31 RPR (Ex. 11) 500° C. O wt % 2.25/1 15 min neat Ca(H2PO) + (very good 1 wt % paste? putty) HPO (aq) 32 HYPR monetite 3.5M 1/1f1 35 min. (Ex. 15) + NaOHAk. (good *12 min. RPR (Ex. 11) 500° C. Soln. paste? putty) 33 HYPR monetite 3.5M 1/3/2 38 min. (Ex. 15) + NaOHAk. (paste/putty) *15 min. RPR (Ex. 11) 500° C. Soln. 34 HYPR monetite Saline, 1/1f1 43 min. (Ex. 15) + EDTA (good *20 min. RPR (Ex. 11) 500° C. buffered paste? putty) *= Set Time at 37° C., 98% Relative Humidity. HYPR monetite = HYdrothermally PRocessed monetite (CaHPO). RPR = Reduction-oxidation Precipitation Reaction. 45S5" glass = {24.5% CaO-24.5% NaO-6% P.O.5-45%. SiO, (wt %)}. PAA = Polyacrylic acid. Commercial ?-TCP from Clarkson Chromatography Products, Inc. (S. Williamsport, PA)
45 fired Solid were conducted as described in Example 1. Example 35 Results are as follows (see FIGS. 18A & B): Novel Low Temperature Neodymium Phosphate Powder Preparation Heated to 500° C., 45 min. (Major) Neodymium phosphate hydrate An aqueous solution of 11.04 g of 50 wt.%HPO was 50 diluted with 5.00 g distilled water to form a clear, colorless Heated to 700° C., 45 min. (Major) Monaazite-NdINdPO solution contained in a 250 ml fluoropolymer resin beaker on a hotplate/magnetic Stirrer. Added to this Solution was 36.66 g neodymium nitrate hexahydrate salt, Nd(NO)- Example 36 6H2O (Alfa/Aesar reagent #12912, CAS #16454-60-7), 55 equivalent to 32.90 wt % Nd. The molar ratio of the Nd/P in Novel Low Temperature Cerium Phosphate Powder this mixture was 1/1 and the equivalent Solids level (as Preparation NdPO) was 38 wt %. Endothermic dissolution of the An aqueous solution of 11.23g of 50 wt.%HPO was neodymium nitrate hexahydrate Salt proceeded with gradual diluted with 5.00 g distilled water to form a clear, colorless warming of the reaction mixture, eventually forming a clear, 60 solution contained in a 250 ml fluoropolymer resin beaker homogeneous lavender Solution at room temperature. Heat on a hotplate/magnetic Stirrer. Added to this Solution was ing of this Solution with constant agitation to approximately 36.94 g cerium nitrate hexahydrate salt, Ce(NO)-6H2O 70° C. initiated a vigorous endothermic reaction which (Johnson-Matthey reagent #11329-36), equivalent to 32.27 resulted in the evolution of NO, , rapid temperature wt % Ce. The molar ratio of the Ce/P in this mixture was 1/1 increase of the sample to approximately 100 C., and finally, 65 and the equivalent solids level (as CePO) was 37.6 wt %. formation of a pasty lavender mass. Heat treatment of the Endothermic dissolution of the neodymium nitrate hexahy pasty Solid and Subsequent X-ray diffraction analysis of the drate Salt proceeded with gradual warming of the reaction US 6,325,987 B1 25 26 mixture, eventually forming a clear, homogeneous colorleSS colorless Solution at room temperature. Heating of this Solution at room temperature. Heating of this Solution with Solution with constant agitation to approximately 75 C. constant agitation to approximately 65 C. initiated a Vig initiated a vigorous endothermic reaction which resulted in orous endothermic reaction which resulted in the evolution of NO, rapid temperature increase of the sample to the evolution of NO, rapid temperature increase of the approximately >100 C., and finally, formation of a pasty sample to approximately >100° C., and finally, formation of light grey mass. Heat treatment of the pasty Solid and a pasty white mass. Heat treatment of the pasty Solid and Subsequent X-ray diffraction analysis of the fired solid were Subsequent X-ray diffraction analysis of the fired solid were conducted as described in Example 1. Results are as follows conducted as described in Example 1. Results are as follows (see FIG. 18C): (see FIG. 18D):
Heated to 700° C., 45 min. (Major) Monazite-Ce CePO Heated to 700° C., 45 min. (Major) Xenotime IYPO, 15 Example 37 Example 38 Novel Low Temperature Yttrium Phosphate Powder Preparation A wide variety of minerals can be made in accordance An aqueous solution of 14.36 g of 50 wt.%HPO was with the the present invention. In the following two tables, diluted with 5.00 g distilled water to form a clear, colorless oxidizing and reducing agents are listed. Any of the listed solution contained in a 250 ml fluoropolymer resin beaker oxidants can be reacted with any of the listed reducing on a hotplate/magnetic Stirrer. Added to this Solution was agents and, indeed, blends of each may be employed. Appropriate Stoichiometry will be employed Such that the 41.66 g yttrium nitrate hexahydrate salt, Y(NO)-6H2O 25 (Alfa/Aesar reagent #12898, CAS #13494-98-9), equivalent aforementioned reaction is caused to proceed. Also specified to 23.21 wt % Y. The molar ratio of the Y/P in this mixture are possible additives and fillers to the reactions. The was 1/1 and the equivalent solids level (as YPO) was 32.8 expected products are given as are Some of the expected wt %. Endothermic dissolution of the yttrium nitrate fields of application for the products. All of the following are hexahydrate Salt proceeded with gradual warming of the expected generally to follow the methodology of Some or all reaction mixture, eventually forming a clear, homogeneous of the foregoing Examples.
Oxidizing Agents Reducing Agents Additives Product(s) Compounds of the form Oxoacids of Group 5B, 6B, Al-O, ZrO2, TiO, SiO, Ca(OH), 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, Cl, 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 ceramic fibers and flake, whisker, granule, Pd, Cd, Sn, Hg, and Pb Hypophosphoric acid particulates, polyacrylic acid, coatings, agglomerates and (HPO); polyvinyl alcohol, polymethyl fine powders. Isohypophosphoric acid methacrylate, polycarbonate, and other (HPO); stable polymeric compounds. Phosphonic acid or Acetates, formates, lactates, simple phosphorus acid (H3PO); carboxylates, and simple sugars. Diphosphonic acid (HPOs); Phosphinic acid or hypophosphorus acid (H3PO). Compounds of the form Sulfur oxoacid compounds: X(NO), or XO(NO), Thiosulfuric acid (HSO); where X = Al, Cr, Mn, Dithionic acid (HSO); Fe, Co, Ni, Ga. As, Y, Polythionic acid (H2S2O); Nb, Rh, In, La, Tl, Bi, Sulfurous acid (H2SO); Ac, Ce, Pr, Nd, Sm, Eu, Disulfurous acid (H2SOs); Gd, Tb, Dy, Ho, Er, Dithionous acid (HSO). Tm, Yb, Lu, U, and Pu Compounds of the form X(NO), or XO(NO), where X = Mn, Sn, Pd, Zr, Pb, Ce, Pr, Th, Th, Pa, U and Pu. Halogen oxoacids: perhalic acid (HOCIO, HOBrOs. HOIO); halic acid (HOCIO, HOBrO, HOIO); halous acid (HOCIO, HOBrO, HOIO) US 6,325,987 B1 27 28 The minerals prepared above may be used in a wide Said reaction evolving nitrogen oxide gas, and variety of applications. Exemplary of these applications are Said calcium phosphate precipitating from Said Solution in pigments, phosphors, fluorescing agents, paint additives, Synthetic gems, chromatography media, gas Scrubber media, wherein Said calcium phosphate is comprised of indi filtration media, bioSeparation media, Zeolites, catalysts, vidual crystallites have a crystal size of about 1 um or catalytic Supports, ceramics, glasses, glass-ceramics, below. cements, electronic ceramics, piezoelectric ceramics, 5. The calcium phosphate produced in accordance with bioceramics, roofing granules, protective coatings, barnacle claim 4 being further derived by heating to a temperature retardant coating, waste Solidification, nuclear waste above about 100° C. Solidification, abrasives, polishing agents, polishing pastes, 6. The calcium phosphate produced in accordance with radiopharmaceuticals, medical imaging and diagnostics claim 5 wherein Said heating is to a temperature below about agents, drug delivery, excipients, tabletting excipients, bio 700° C. active dental and orthopaedic materials and bioactive 7. The bioactive and biocompatible calcium phosphate of coatings, composite fillers, composite additives, Viscosity claim 4 wherein Said phosphorus oxoacid is hypophospho adjustment additives, paper finishing additives, optical 15 rus acid. coatings, glass coatings, optical filters, fertilizers, Soil 8. A bioactive cement for the repair of osseous defects nutrient(s) additives. comprising the bioactive and biocompatible calcium phos What is claimed is: phate of claim 4. 1. A Substantially homogeneous calcium phosphate Salt 9. The bioactive and biocompatible calcium phosphate of that is an oxidation-reduction product formed by: claim 4 admixed with a pharmaceutically acceptable carrier preparing an aqueous Solution comprising: or diluent. a metal cation which is calcium; 10. The bioactive and biocompatible calcium phosphate at least one oxidizing agent, and of claim 4 admixed with a polymerizable material. at least one precursor anion oxidizable by Said oxidiz 11. An alkaline earth phosphate Salt of an oxidation ing agent to form a phosphate, and 25 reduction product formed by: heating Said Solution under conditions of temperature and preparing an aqueous Solution comprising preSSure effective to initiate an oxidation-reduction an alkaline earth cation; reaction between Said oxidizing agent and the precursor at least one oxidizing agent, and anion; Said reaction evolving at least one gaseous product; and giving rise to Said phosphates Said metal at least one precursor anion oxidizable by Said oxidiz phosphate, Salt precipitating from Said Solution, and ing agent to form a comprised of individual crystallites having a crystal phosphate, and size of about 1 micron or below. heating said Solution under conditions of temperature and 2. The calcium phosphate Salt of claim 1 having Substan preSSure effective to initiate an oxidation-reduction tially uniform morphology. 35 reaction between Said oxidizing agent and the precursor 3. The calcium phosphate Salt of claim 1 having a anion, Said reaction evolving at least one gaseous non-Stoichiometric composition. product; and giving rise to Said phosphate, Said alkaline 4. Substantially homogeneous, bioactive and biocompat earth metal phosphate Salt precipitating from Said Solu ible calcium phosphate that is an oxidation-reduction prod tion wherein Said alkaline earth metal phosphate Salt is uct produced by: 40 Substantially homogeneous and has a Substantially fine preparing an aqueous Solution of a phosphorus Oxoacid crystal size of about 1 um or below, wherein Said and a calcium nitrate; alkaline earth metal is calcium. heating said solution to a temperature of about 250 C. or 12. The alkaline earth metal phosphate salt of claim 11 below under conditions of temperature and preSSure 45 having a non-Stoichiometric composition. effective to initiate an oxidation-reduction reaction between the oxoacid and the calcium nitrate; k k k k k