CA1279175C

CA1279175C - Ceramic processing and products

Info

Publication number: CA1279175C
Application number: CA000526432A
Authority: CA
Inventors: Ronald L. Salsbury; Don J. Henderson
Original assignee: Orthomatrix Inc
Current assignee: LIFE CORE BIOMEDICAL Inc
Priority date: 1985-12-31
Filing date: 1986-12-29
Publication date: 1991-01-22
Anticipated expiration: 2008-01-22
Also published as: EP0250570A1; WO1987004110A1

Abstract

ABSTRACT
The invention disclosed by this application relates to a novel method of processing sinterable powders into sintered ceramic products involving agglomeration of fine particles with a binding agent and extraction of the binding agent from the agglomerates prior to sintering. This application also relates to novel forms of aluminum oxide, hydroxylapatite, and tricalcium phosphate ceramic products prepared in accordance with the method of this invention, as well as novel intermediate products useful to prepare the novel ceramic products of this invention.

Description

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~ERAMIC PROCE$SING AND PROD~ÇTS
1 Field of ~he Invention 2 The invention di~clo5ed in thig application relates 3 to a novel method of procegsing sinterable powders into 4 sintered oeramic products involving agglomeration of fine particles with a binding agent and extraction of the binding 6 agent from the agglomerates prior to sintering. This 7 application also relates to novel forms of aluminum oxide, 8 hydroxylapatite, and tricalcium phosphate eeramic products 9 prepared in accordance with the method of this invention, as well as novel intermediate products useful to prepare the novel 11 ceramic products of this invention.
12 ~ACKGROUND OF THE INVENTION
13 Bone prostheses are often needed for temporary or 14 permanent use in man or animals. A wide variety of different biocompatible materials have been developed for use a~ bone 16 prostheses, including, for example, natural or synthetic 17 mineral materials, metals, such as Vitallium~, stainless steel 18 and chromium alloys, as well as organic resin~, such as 19 silicone rubbers. The foregoing materials may be employed, for example to: (1) replace a portion of bone which has been lost 21 due to accident or disease, or (2) reinforce a portion of bone 22 which has atrophied or suffered a reduction in mineral content.
23 In some individuals the alveolar ridge becomes 24 abnormally thin and unable to support either natural or artificial teeth. The support or rebuilding of the alveolar 26 ridge has, therefore, become an important step in the treatment 27 of those individuals suffering from a weakening in the alveolar 28 ridge due to periodontal disease or other causes. Mineral 29 materials of both synthetic and natural origins have been emplo d for bone restorative purposes in the alveolrr ridge ~ ¦

~1 _~

lZ'-~9175 1 and, hence, to prevent tooth los~ due to bone loss in the 2 alveolar ridge.
3 Many of the same synthetic and naturally occurring 4 biocompatible materials which have been employed for bone prostheses have also been employed for dental restorative 6 purposes. In particular, calcium pho~phates, such as 7 hydroxylapatite, tricalcium phosphate (whitlockite) and 8 mixtures thereof have been widely reported in the literature as 9 suitable ~or use as bone prosthesis as well as for dental l¦ restorative purposes~ See, e.g. Monroe, et al., J.Dent.Res.
11 l 53, p. 1353 et seq. (1974); Bett et al., J.A.C.S, 89, p.5335 et 12 l seq. (19S7); Rutty, Indian J.Chem. 11, 695 (1973).
13 Hydroxylapatite is a naturally occurring mineral 14 present in phosphate rock. Hydroxylapatite also constitutes the mineral portion of natural bone and tooth. As such it is 16 highly biocompatible and has a thermal coefficient of expansion 17 I quite similar to tooth enamel.
18 ~s discussed in greater detail below, in accordance 19 with the preferred embodiments of the method of this invention, fine dry particles of a hydroxylapatite powder are agglomerated 21 with a binding agent into sinterable spheroidal agglomerates.
22 The binding agent is removed from the spheroidal agglomerates 23 ¦ and then they are sintered to provide spheroidal ceramic 24 particles of hydroxylapatite having a uniform network of micropores extending throughout the ceramic product.
26 1 U.S. Patent No. 4,097,935 (hereinafter '935) sets 27 forth a description of a method for preparing a maximally 28 densified, pore-free hydroxylapatite ceramic body. In 29 accordance with the '935 patent the dense, pore-free ceramic body cescribed thereln may be prepared by sintering (under .
j ~2~ s 1 1 specified conditions) a shaped body or mass prepared from an 2 I aqueous gelatinous precipitate 4~ hydroxylapatite. The '935 3 patent teaches away from the use of both products and processes 4 ! which employ fine particles of hydroxylapatite as starting I materials in the preparation oi~ the dense, pore-free ceramic 6 li products described in the '935 patent- In this regard the '935 7 ~I patent states:
8 ¦ "It is critical, in the above process, to prepare the hydroxylapatite as a gelatinous 9 precipitate from aqueous solution for it is only in this cohesive gelatinous state that ! hydroxylapatite can be shaped or molded and then dried and sintered to produce a ceramic 11 body. Dry particulate or granular hydroxylapatite cannot be reconstituted into 12 the cohesive gelatinous state.. Moreover although powdered hydroxylapatite can be 13 compressed into a shaped body, such as a tablet, when sintered according to the 14 method of this invention the product obtained is highly porous and does not fracture along smooth planes but simply 16 shatters." (Col. 9, lns. 22-39).
17 ¦ In contrast to the foregoing, the method of this 18 ! invention employs dry particulate hydroxylapatite as the 19 ¦ starting material in a novel method employed to prepare porous hydroxylapatite ceramic particles having a network of 21 micropores extending throughout the ceramic product.
22 The '935 patent also discloses means for introducing 23 pores into the ceramic bodies produced in accordance with the 24 method described in that patent. In this regard the '935 ~ patent states that pores may be introduced by drilling or 26 1 machining holes in the non-porous ceramic product, or by mixing 27 ¦ an organic binder with a body of the gelatinous hydroxylapatite 28 1 precipitate pr:ior to s-ntering. The binder is said to j volatilize during sintering to produce pores in the ceramic product. The ~:intered body would ehen have to be ground, or ~ ¦
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1 comminuted in 80me other way to provide a particulate ceramic 2 product.
3 Unlike the method described in the '935 patent, in 4 accordance with applicant's method, a bindin~ agent is not added to a gelatinous precipitate of hydroxylapatite, and in 6 producing applicant's final ceramic it is not a sinterable body 7 prepared by adding a binding agent to an aqueous gel which is 8 ultimately sintered. Rather, contrary to the method described 9 in the '935 patent, in accordance with applicant's method the binding agent is employed to agglomerate together fine dry 11 particles of hydroxylapatite, and it is applicant's novel 12 agglomerate of dry hydroxylapatite particles which is sintered 13 in accordance with the method of the present application.
14 ~iocompatible compositions suitable for use as a dental filling material have been prepared by mixing finely lS divided ceramics such as sintered hydroxylapatite with a 17 hardenable binder material. In addition, moist ceramic 18 particles of hydroxylapatite have been employed as a 19 biocompatible packing material to fill the voids or lesions caused by advanced periodontal diseases. The ceramic particles 21 used have typically been employed in the orm of very finely 22 divided ceramic powders made up of particles in the range of 23 about 10 to about 60 mesh.
24 Fine particles of calcium phosphate ceramics suitable for use in such filling or packing compositions may be prepared 26 by grinding larger particles or masses of the ceramic down to 27 fine particles within the desired particle size range. The 28 grinding step may be conducted before or after sintering.
29 However, in order to obtain a ceramic powder made up of j¦ parti es within a desired size range, particles larger and ¦
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;~ ~L291~5 1 particles smaller than desired must be separated by sieving or 2 by another particle classification process, from the mass of 3 particles produced by the grinding step. Thus, grinding 4 processes typically yield a fraction of ceramic particles which are smaller than the desired particle size range, and which are 6 often simply discarded as waste. Moreover, the ceramic 7 ¦ particles produced by grinding are typically not uniform in 8 ¦ shape, and possess sharp edges or "points" which could lead to 9 local inflammation when placed in contact with tissue. It will be appreciated by those skilled in the art that the term "mesh"
11 as used herein refers to particle size as determined on 12 standard sieves and that while there is some variation in the 13 screen size used with different standards those variations are 14 so small, e.g., See, Kirk-Othmer Encyclopedia of Chemical Technology 18:318-319, 2d ed. (1969), that they are 16 j insignificant for purposes of this invention. Accordingly, the l? mesh sizes may be measured in accordance with e.g., U.S. Bureau 18 of Standards, British Standard, Tyler Standard, or the like.
19 Ground hydroxylapatite particles and other ceramic particles having sharp edges or points can be mechanically 21 treated to render the particles substantially spheroidal in 22 shape and smooth. However, such mechanical procedures involve 23 extensive milling to remove the sharp edges from the ceramic 24 particles. The process itself is very cumbersome, and the yields guite low.
26 Conventional molding, casting or pressing operations, 27 j which do not involve grinding or milling, are generally 28 1 suitable for the preparation of smooth round ceramic particles~
29 However, in the case of calcium phosphate and other ceramics 1 intenttd or use in bone or tooth restorative compositions, ~7~9175 1 ll particles on the order of 20-40 mesh are often desired, and 2 ¦ such particles are too small to be produced by such 3 conventional fabrication processes known to be useful to 4 prepare round smooth particles.
¦ It is an objective of this invention to provide a 6 ¦¦ substantially waste-free, high-yield, ceramic particle~forming 7 ¦¦ process which may be employed to prepare ceramic particles 8 , which are substantially spheroidal in shape, and are within a 9 ! desired particle size range.
¦ It is a particular objective of this invention to 11 ~ provide a high-yield process for the preparation of 12 ¦ biocompatible ceramic particles, especially particles of 13 ! calcium phosphate and aluminum oxide ceramic which are 14 substantially spheroidal in shape and within about the 10 to ¦ about 80 mesh range. The spheroidal ceramic particles produced 16 l by the process of this invention are free of sharp edges or 17 ridges capable of producing local irritation when placed in 18 contact with tissue. As such, the spheroidal ceramic particles 19 of this invention are suitable for use as the ceramic component ,l of hardenable binder compositions formulated for use for dental 21 I or bone restorative processes.
22 l BRIEF DESCRIPTION OF THE INVEN~ION
23 ~ In accordance with the foregoing, this invention 24 I provides a high-yield method for preparing sintered ceramic ¦
¦ particles which comprises the steps of binding together fine 26 particles of a sinterable inorganic powder to provide 27 ! sinterable particulate agglomerates within a desired size 28 ¦I range. The fine particles of the sinterable powder are bound 29 1I together to form the agglomerate with a binding agent, such as 30 ¦I polyvinyl alcohol, hydroxypropyl oellulose, polyvinyl l ll -~ l 12~9 1 pyrrolidone, starch, pregelatinized starch or the like. The 2 binding agent is removed by an extraction step and the 3 agglomerate may then be sintered to provide the final 4 particulate ceramic product.
In the preferred embodiments of the method of this 6 invention, fine particles of sinte~rable hydroxylapatite and/or 7 ¦ whitlockite are agglomerated together with a binding agent to 8 provide sinterable agglomerates which are spheroidal in shape.
9 The agglomerate is subjected to liquid extraction or elevated l temperatures in order to substantially eliminate the binder 11 from the agglomerate prior to subjecting the agglomerate to 12 higher temperatures in order to complete the sintering process.
13 It has been found that when the calcium phosphate 14 (e.g. hydroxylapatite and/or tricalcium phosphate) based lS agglomerate of this invention is sintered at elevated 16 l temperatures, the individual inorganic partlcles which comprise 17 1 the agglo~erate meld together to provide strong, free-flowing, 18 structurally stable ceramic particles. In addition, the 19 finally sintered agglomerate will include a network of I micropores extending throughout the particles. Advantageously, 21 the microporous structure of the particle provides sites for 22 tissue ingrowth and attachment, while the smooth surface of the 23 particles prevents the inflammatory response noted in 24 connection with the rough and irregular surfaces of untreated ground ceramics.
26 In addition to the advantages mentioned above, the 27 ¦ ceramic particle-forming process of the invention may be 28 ¦ conducted such that only a minor amount of the finely powdered 29 ceramic ~tarting material is wasted. In accordance with the process of this invention, agglomerates which are smaller than ~ ~LZ~917S ~

1 desired, or any starting ceramic powder which is not 2 agglomerated, may be reused in a subsequent agglomerating 3 process. Similarly, agglomerates which are larger than desired 4 may simply be re-ground and used in a subsequent agglomerating ~ process.
6 I DETAILED DESCRIPT:CON OF THE INVENTION
7 !l In accordance with the first step of the process of 8 !I this invention, sinterable agglomerates are prepared by g ¦l adhering together fine particles of sinterable powder with a l; binding agent. The binding agent may be any material which ~ effects adhesion between the particles to be agglomerated, and 12 l¦ can be eliminated from the agglomerates without leaving a 13 ¦¦ residue that interferes with the sintering or biological 14 I properties of the finished product. Suitable binders include organic polymers, preferably polyvinyl alcohol, polylactic 16 acid, hydroxylpropyl cellulose, starch, pregelatinized starch 17 l and polyvinyl pyrrolidone.
18 The initial particle size of the fine sinterable 19 ¦ powder starting material employed to form the agglomerate is preferably in the range of about 1 to about 75 microns, and 21 most preferably in the range of about 5 to about 50 microns.
22 The fine sinterable powder may be prepared by conventional 23 ¦ methods, such as by grinding or milling larger particles or 24 masses of a sinterable material. ~owever, as described in greater detail below, it is preferred to prepare the finely 26 divided ceramic powder by a spray-drying process. Spray-dryi~g 27 ¦ is preferred because it provides a better than 90% yield, 28 ¦ provides particles within a narrow particle size range, and 29 ¦¦ provides an easy-to-handle, free-flowing powder.
3~ 1~ The sinterable agglomerate may be prepared by I

1 ¦ ~applyi the binding agent ~or a solution of the binder) to a 2 fluidized bed of the ceramic powder. ~or example, dry and 3 finely ground hydroxylapatite powder may be char~ed into a 4 Glatt Powder Coater, Model No. GPCG 5-9 (manufactured by Glatt-Air Techniques, Inc. of Ramsey, New Jersey) which 6 fluidizes and agitates the powder particles, while the binder 7 I is fed at a controlled rate onto the fluidi~ed bed of 8 j particles. In the Glatt Powder Coater the fine powder is 9 I fluidized by the introduction of a stream or jet of air into ¦ the device which "puffs up" the powder particles and suspends 11 ¦ them in air. At the same time the powder is agitated in a 12 I rotary fashion in the Powder Coater When the binding agent is 13 sprayed onto the rotating, fluidized bed, the powder particles 14 agglomerate into larger and larger sized agglomerates in a snow-ball-like fashion, as the amount of binder added to the 16 bed increases. The resultant agglomerates are substantially 17 spheroidal in shape.
18 As an alternative to spraying the binder onto the 19 fluidized bed of fine sinterable particles, the binder may be added as a solid dispersed within the fluidized bed of fine 21 sinterable particles. In this embodiment of the process, the 22 fluidized bed of the initially added sinterable particles and 23 binder may be sprayed with a suitable liquid, for example, 24 water or an aqueous or other solution of the binder.
For example, following the techniques discussed 26 above, hydroxylapatite powder, having a particle size in the 27 range of about: 1 to about 75 microns, may be aggl~merated with 28 an organic binder until agglomerates in about the 10 to about 29 80, preferably about 20 to about 70 mesh range, are formed.
3~ The sint red ceramic is typically somewhet smaller in size than .. . _ . .

~'2~91~

1 the agglomerate from which it is pre~ared. Thus, it is 2 preferred to sinter agglomerates within a particle size range wherein the largest agglomerates are about 15 - 75% larger, 4 preferably about 30% larger, than the largest ceramic particle desired; while the smallest ~gglomerates are also about lS -6 75% larger, preferably about 30% larger, than the smallest 7 ceramic particles desired. Thus, prior to sintering, it is 8 preferred to classify the group of particles which are produced 9 by the agglomeration step in order to select agglomerated particles within the appropriate particle size range. The 11 classification of particles may be conducted by sieving, or by 12 any other conventional sorting or particle classification 13 technique.
14 One of the advantages of the process of this invention is that off-sized agglomerates or any non-16 agglomerated starting material may be recycled. That is, 17 agglomerated particles which are smaller than desired can 18 simply be reused in a later batch, while agglomerates that are 19 too large may be ground to a smaller size, and reused during a subsequent agglomeration process. Thus, there should be little 21 or no waste reulting from the agglomeration process. Moreover, 22 as shown by the following Examples, the sinterin~ process may 23 yield 90% or more of sintered ceramic particles within the 24 desired particle size range.
In further embodiments of the method of this 26 invention, the agglomerated particles produced in the manner 27 described above may be employed as core or seed particles in a 28 second agglomerat;on process. During the second agglomeration 29 process, the previously prepared core particles, which is I itself an agglomerate, may be coated with additional layers of ~ -10-.1 12~9175 ~ ¦
I
1 binder plus additional fine ceramic particles. Through this 2 embodiment of the method of this invention, one can prepare a 3 sinterable agglomerate made up of a core of one ceramic 4 material, over which a plurality of spheroidal shells or layers of the same or a different ceramic material are formed.
6 Through this embodiment one may ,also prepare a sinterable 7 agglomerate of hydroxylapatite made up of a core of a given 8 density over which one or a plurality of shells or layers may 9 ¦ be formed having a different density than the core agglomerate.
A shell or layer may also be applied to the core particle which 11 is made up of an hydroxylapatite having a particle size which 12 is different from the hydroxylapatite particles which make up 13 the core of the sinterable agglomerate.
14 The sinterable agglomerates of this invention ¦ preferably are comprised of about 5~ to about 25% by weight of 16 the binder, preerably about 10% to about 15% of the binder, 17 while the agglomerate preferably comprises about 75% to about 18 90%, and preferably about 85% to about 95% by weight of 19 sinterable ceramic particles of hydroxylapatite, and/or whitlockite or aluminum oxide. Moreover, the bulk density of 21 the agglomerate is preferably about 0.8 to about 1.5 grams/cc, 22 for agglomerates within about the 10 to about 80 mesh range, 23 while for the preferred agglomerates of hydroxylapatite, the 24 bulk density is about 1 to about 1.2 grams/cc for agglomerates in about the 15 to about 30 mesh range.
26 It should be noted that the sinterable powder 27 employed to form the agglomerate may be in the form of 28 irregularly shaped particles which possess microscopic ridges 29 1 or points. When these very fine particles are agglomerated ~ into the larger agglomerates (typically in about 10-80 mesh ~~ ~

~L27~1~5 1 range) and then sintered, the larger sintered ceramic particle 2 possesses a macroscopically smooth surface. In contrast, 3 ceramic particles in the 10-80 mesh range prepared, for ~ example, by grinding larger ceramic particles possess larger ¦ surface points or ridges. It is the larger ridges or points of 6 1 the ground ceramic materials which present a dan9er of local 7 1 irritation when such ceramics ~re placed in contact with 8 ~ tissue.
9 ¦ The agglomerates of this invention are sintered to ! provide the finished particulate ceramic product. The 11 ¦ temperature and duration employed to sinter the agglomerate may 12 ¦ be the same as those one would conventionally employ to sinter 13 the sinterable powder from which the agglomerate was prepared.
14 ¦ However, the binder may advantageously be substantially ¦ eliminated before the agglomerate reaches the more elevated 16 ¦¦ sintering temperatures by liquid extraction or heating of the 17 ¦1 agglomerate to a first temperature that is less than the 18 ! sintering temperature. Preferrably, about 75 to 90 wt. percent 19 or more of the binder is removed from the agglomerate particles by the extraction step prior to sintering. If an agglomerate 21 from which excess binder has not been extracted were rapidly 22 heated to sintering temperatures, there is a danger that any 23 ¦ excess binding agent present could affect the color of the 24 finished product, e.g., carbonize and produce a dark off-color in the ceramic product.
26 ¦ In one embodiment of the method of this invention, 27 I the hydroxylapatite-containing agglomerate is subjected to a 28 I preliminary heat treatment, i.e., heat extraction of the 29 1¦ binding agen~, at a temperature sufficient to eliminate a 1 substantial portion of the binder from the agglomerate leaving 12~9~7~;

1 at least a sufficient amount of binder so as not to adversely 2 affect the adhering of the particles present in the agglomerate c~ rn e, r 4;te~
3 and to provide an ~glo~e~te which may sintered without 4 objectionable coloration by c2lrbonization. This preliminary heat extraction is preferably conducted at temperatures below 6 about 700C, and more preferably about 500 C or less. Heating 7 is preferably effectuated in an oven at the rate of about 20C
8 per minute up to the final temperatures set forth above.
9 Results may be improved by enriching the oven air or other atmosphere with oxygen. However, the actual temperature, 11 heating rate and oven atmosphere employed will be a function of 12 the particular binder selected, air flow in the oven, etc. It 13 has been found that the foregoing heat extraction serves to 14 substantially eliminate the binder while nevertheless providing a structurally-stable agglomerate of hydroxylapatite. The 16 extracted agglomerate of hydroxylapatite particles may then be 17 subjected to elevated sintering temperatures without fear o 18 discolorization due to carbonization of the binder or other 19 adverse effects on the product. The resultant ceramic particle 2~ is preferably white, not translucent and biocompatible.
21 Alternatively, or in addition to heat extraction the 22 binding agent may be removed from the agglomerates with a 23 liquid extraction technique. Liquid extraction involves 24 washing the agglomerates in a liquid preferably a solvent for the binding agent, e.g., isopropyl alcohol, methylene 26 dichloride, methanol and aqueous solutions thereof. Such 27 aqueous solutions may contain about 99 to 80% by wt. organic 28 solvent. The presently preferred solvent is 100% isopropyl 29 alcohol. The particular solvent used and extraction conditions employ wil1 depend Dn the particu1ar binding agent and ~ qZ7917~ ~

1 agglomerate to be treated and enough binding agent should 2 remain in the agglomerate after extraction to prevent 3 disintegration of the agglomerate prior to sintering. To 4 effect liquid extraction the agglomerates may be submerged in the liquid for a sufficient period of time, e.g., about 2 or 6 more hours, to substantially eliminate the binding agent from 7 the agglomerate. Heating or boiling the liquid containing 8 submerged agglomerate may accelerate the extraction process 9 and/or enhance the effectiveness of the extraction. A typical liquid extraction involves charging about 1 liter of isopropyl 11 alcohol into an extraction chamber of a Soxhelt-type extractor.
12 Then about 1.5 kg of agglomerated hydroxylapatite including a 13 polyvinyl pyrrolidone binder prepared as described above is 14 mixed with the aqueous isopropyl alcohol and the mixture is heated to reflux for about 72 hours. Thereafter, the liquid 16 containing extracted binding agent Ipolyvinyl alcohol) i5 17 separated from the agglomerate and the agglomerate is dried to 18 constant weight at about 80-110C.
19 Regardless of the extraction technique employed sufficient binder is preferrably removed from the agglomerate 21 to prevent adverse effects on subsequent sintering and/or the 22 physical properties performance and biocompatibility of the 23 finished product. However, if desired an amount of binder may 24 be maintained in the agglomerate to facilitate further processing without undesirable disintegration of the 26 agglomerate particles.
27 For the preferred agglomerate of hydroxylapatite 28 powder sintering is conducted at a temperature of about 1000C
29 to 1300C for about 1 to about 5 hours, most preferably at about 1075C to 1250C for about 1 to about 3 hours.

1~91'7~
Fine sinterable hydroxylapatite powder suitable for agglomeration may be prepared by any conventional granulating and/or particle sorting technique. Preferably, however, the fine particulate hydroxylapatite starting material employed herein is prepared by first preparing a gelatinous aqueous precipitate of hydroxylapatite, and then processing the precipitate into a sinterable fine dry powder suitable for use in the agglomeration process.
A suitable procedure for the preparation of an aqueous gel of hydroxylapatite is described by E. Hayek et al., Inorganic Synthesis, 7, 63 (1963). Hayek et al. disclose the precipitation of hydroxylapatite using phosphate solution, in accordance with the following reaction scheme:
5Ca(NO3) 2+ (NH4)3PO4+NH40H --> Ca~(oH)(po4)3+loNH4No3.
The reaction disclosed by Hayek et al. leads to a gelatinous precipitate of hydroxylapatite which must be maintained in contact with the original solution or mother liquor until the molar ratio of calcium to phosphorus in the precipitate reaches the stoichiometric proportions characteristic of hydroxylapatite, i.e., about 5:3 or 1.67.
Once the stoichiometric proportions of calcium and phosphorus characteristic of hydroxylapatite are obtained, the gelatinous precipitate is separated from the mother liquor, and the precipitate is washed to substantially reduce or, if desired, to eliminate the ammonium nitrate present in the gelatinous product. Since ammonium nitrate decomposes into gaseous by-products at temperatures of about 180C to about 300C, the generation of gas from ammonium nitrate during the heating of the agglomerate can lead to a breakup or weakening ~' ' :

~ ~2~ L7S

1 ~oE the agglomerated hydroxylapatite precipitate by re-2 suspending the precipitate in water, centrifuging the 3 suspension, and then decanting t:he water.
4 The gelatinous precipitate of hydroxylapatite is next ¦dried and converted into fine pdrticles. The foregoing may be 6 iaccomplished by way of a number of different drying or 7 ¦granulating techniques. Drying techniques which can be used 8 !include, for example, tray drying, vacuum drying, etc. If 9 ~ desired, the dried particles may be ground and then classified 1 in order to obtain particles within the desired particle range.
11 Spray drying is the preferred technique for 12 ¦¦ converting the gelatinous precipitate of hydroxylapatite into 13 I the fine dry particles suitable for use in the agglomeration 14 process. The gelatinous precipitate may be spray dried by first preparing an aqueous slurry of the precipitate suitable 16 for spray drying. The slurry may have a solids content of 17 ! about 5% to about 15%, preferably about 7% to about 10% by 18 1¦ weight, and the slurry may then be spray dried to provide 19 ¦I particles within the desired size range.
ll Spray drying may be conducted at temperatures of less 21 ¦ than 400C, e.g., in a conventional spray dryer employing an 22 ¦ air inlet temperature of about 250C, and an outlet temperature 23 of about 115C. Under these conditions the spray-dried 24 hydroxylapatite particles are in a substantially anhydrous state, and the hydroxylapatite is no longer gelatinous, but may 26 contain some chemically bound water. The spray-dried product 27 obtained is in the form of dry porous particles of hydroxy-28 ll lapatite which cannot be reconstituted into the gelatinous 29 I state by the addition of waterO Moreover, the spray-dried ¦ particles of hydroxylapatite are substantially spheroidal in --~ ~279~75 ---1 shape.
2 The finally sintered hydroxylapatite agglomerates of 3 this invention preferably have a porosity sufficient to permit 4 the desired degree of tissue ingrowth to ensure proper attachment when the ceramic is employed for prosthetic purposes 6 or as an implant material. The preferred hydroxylapatite 7 ceramic produced in accordance with this invention is 8 ¦ substantially spheroidal in shape and has a bulk particle 9 ¦ density of about 80% to about 95~ of the theoretical maximum ! density of pure hydroxylapatite. Moreover, the ceramic 11 ¦ hydroxylapatite product includes an extensive network of 12 ¦ micropores extending throughout the product, as seen by 13 Scanning Electron Microscopic analysis. The individual pores 14 which form the network are preferably all less than about 40 to about 50 microns (maximum pore diameter) in size. Most ~ ~o-h . .
V 16 preferably, the medi~ pore size is about 1.5 microns as 17 determined by mercury porosimetry, with about 90% of the pores 18 being less than about 0.3 microns.
19 In further aspects of this invention, the finely sintered ceramic particles produced by the method of this 21 invention may be combined with an orally compatible binder 22 material and employed as a dental restorative material used to 23 fill lesions caused by periodontal disease, or to augment or 24 restore the alveolar ridge. The dental restorative compositions may also be employed as a tooth filling material, 26 a dental liner, to mold or cast artificial teeth, etc. The 27 spheroidal ceramic particles of this invention which employ 28 pure hydroxylapatite are preferred for use in such dental 29 restorative cornpositions because hydroxylapatite possesses a ¦ thermal coefficient of expansion substantially identical to ... . ,.i..,."~ ,,...,, ,._.c ~ 12'79175 1 that of natural tooth enamel, the hardnes5 of hydroxylapatite 2 is similar to the hardness of natural tooth, and in addition 3 natural tooth and hydroxylapatite stain in a similar way.
4 The preferred dental restorative compositions of this ¦ invention are comprised of about 5~ up to about 90% by weight 6 of the hydroxylapatite ceramic of this invention dispersed 7 within about 10~ to about 95~ by weight of an orally compatible 8 secondary binder.
9 Suitable binders for use in the preparation of the ¦ dental restorative materials of this invention, and 11 ! particularly those employed to augment or restore the alveolar 12 ¦¦ ridge, or to fill periodontal lesions, include secondary 13 binders such as a binder comprised of plaster of paris (calcium 14 sulfate hemihydrate) and water. Alternative secondary binding materials include polymeric or polymerizable materials in 16 combination with the appropriate additives for hardening the 17 binder, e.g., crosslinking agents, polymerization catalysts, 18 diluents, etc.
19 The polymeric or polymerizable secondary binder may be selected from a broad group of known polymeric materials 21 suitable for use in the oral cavity. Such materials include, 22 ¦ for example polymethacrylates such as hydroxylethylmetha-23 1 crylate, polymethylmethacrylate, as well as other polyacrylic 24 acids or esters, epoxy resins, polyesters, etc.
In addition, the ceramic particles produced in 26 accordance with this invention may be admixed with a 27 biocompatible inorganic or organic secondary binder, and then 28 cast or molded into the form of a tooth, bone, a portion of a 29 bone, etc. Bone prostheses prepared in this manner may then be surgically implanted employing conventional surgical -lC-17~79~7S

1 techniques.
2 The spheroidal ceramic hydroxylap~tite of this 3 invention is also particularly well suited for use as a 4 surgical implant material. For example, moist spheroidal particles of the hydroxylapatite ceramic in the cize range of 6 about 10 to 60 mesh may be used to fill properly prepared 7 lesions caused by periodontal Idiseases. The moist 8 ¦ hydroxylapatite is packed into the lesion following known 9 periodontal procedures. In addition, the ceramic hydroxylapatite ceramic of this invention may be diluted with a 11 biocompatible diluent such as saline solutions or even blood, 12 and injected into or about the alveolar ridge in order to 13 augment or restore portions of that ridge, in accordance with 14 known surgical procedures. For this purpose the spheroidal hydroxylapatite ceramic is preferably in about the 1~ to about 16 1 60 mesh ran~e.
17 When surgically filling or packing a periodontal 18 ¦ lesion or another undesired void with the ceramic particles of 19 ¦¦ this invention, it is desirable to completely fill the void.
¦¦Advantageously, when a periodontal lesion or another void is 21 I packed with spheroidal ceramic of this invention, the ceramic 22 filling substantially retains its original volume with little 23 or no reduction in the volume of the filling material due to 24 the settling of the particles in the void. In contrast, irregularly shaped non-spheroidal particles tend to settle in a 26 void causing an undesired reduction in the volume of the 27 filling material.
28 The crush strength, i.e., friability, of the ceramic 29 particles produced in accordance with the present invention was measured by crushing 5 to 10 uniformly shaped particles (one at -19- ~

Il ~L2~917S

1 ~ a time) of ~0-40 mesh hydroxylapatite agglomerate in a 2 I Chatillon Model 1750~ die shear tester. The average friability 3 ¦ values presented in the following examples are given in pounds 4 I as read directly from the scale on the Chatillon tester.
!j This invention will be described further with 6 I reference to the following detailed Examples.
7 ! I EXAMPLE 1 8 ¦l 45.4 kg of calcium nitrate tetrahydrate was dissolved 9 I~ in 265 liters of deionized water and ~2 kg of 26% ammonia water ~I was added.
~ Separately, 15.2 kg of ammonium phosphate dibasic was 12 ¦¦ dissolved in 378 liters of D.I. water and 28 kg of 26% ammonia 13 li was added. This solution was added into the solution of 14 ¦¦ calcium nitrate under agitation which was then continued for 36 ¦¦ hours at ambien~ temperature. The slurry was then centrifuged 16 ! through a split bowl centrifuge (Centrico, Inc. Model SB7~.
17 ¦ The solids were collected, dispersed in 500 liters of D.I.
18 ¦ water and centrifuged again, dispersed once more in 500 liters 19 I of D.I. water and centrifuged. The collected solid is dried in I a vacuum tray dryer at B0C and 60 mm Hg pressure. Dry hard 21 , white lumps thus obtained were ground in a hammermill to pass ~2 an 80 mesh screen. Yield: 18.90 kg of Ca5(OH)(PO4)3 - 97.9%.

24 45.4 kg of the calcium nitrate was precipitated with I ammonium phosphate exactly as described in Example 1. The 26 ¦~ precipitate was centrifuged and twice redispersed in 500 liters 27 ¦j of D.I. water and centrifuged again. The gelatinous solid was 28 ¦! dispersed in D.I. water again to produce a slurry with 8.3% of 29 l¦ solids which was then spray dried using a Bowen spray dryer.
1l air inlet temperature: 250C

., 1 1 air outlet temperature: 115C
2 1l The product obtained was a white powder having a 3 l¦particle size of about 20-40 microns in the main fraction.
4 ~¦Yield: 17.60 kg of Ca5(OH)(PO4)3 - 91.1%
l¦ EXAMPLE 3 6 ¦¦ 4.0 kg of hydroxylapatite powder prepared as 7 1! described in Example 1 was charged into Glatt powder 8 ¦coater/granulator GPCT 5-9.
9 ¦l 400 g of pregelatinized starch was dissolved in 4600 ¦¦g of D.I. water.
11 1 The rotor was turned on and speed adjusted at 400 12 ¦ rpm, the air let temperature was 70C and a starch solution was 13 ¦¦ sprayed-in initially at 120 g/min., and later at 40 g/min.
14 ¦jHigh initial flow rate is necessary to prevent loss of the dry ¦¦fine powder. Agglomeration was monitored by sieving samples 16 !, taken in approximately 5 min. intervals. Feeding of the starch 17 ¦ solution was discontinued when the desired particle size was 18 reached (approx. 60 min.); material was dried, discharged and 19 sieved.
Yield Sieve Analvsis 21 4.45 kg -- 96.7% ~16 mesh 5.8~
22 16-30 mesh 54.7%
23 -30 mesh 39.5%
24 The fraction 16-30 mesh -- 2.43 kg -- was then charged into alumina crucibles and sintered; the material was 26 heated to the temperature 1200C at the rate of 8t~/min., 27 temperature :L200C was maintained 2 hours, material was cooled 28 !down to 300t' and removed from the furnace at this temperature.
29 1 The product was we`i~hed and sieved again.
¦ Yield Sieve Analysis ~1 !

jl li ''-:J

-` I!
I ~2~917S

1 2.17 kg -- 89.3~ 16-20 mesh 3.8%
2 ¦ - 20-40 mesh 93.5%
3 I -40 mesh 2.7%
4 ¦ EXAMPLE 4 ! 5.0 kg of spray dried hydroxylapatite powder, 6 ¦ prepared as described in Example 2, was charged into the Glatt 7 ¦ GPCG 5-9 granulator.
8 j 400 9 of pregelatinized starch was dissolved in 9 ¦l 4600 c of D.I. water. The rotor was turned on at 400 rpm and 'i starch solution sprayed in at 120 g/min initially, and later at 11 li a rate of 40-60 g/min. Feeding of the starch solution was 12 ~I discontinued when the desired particle size is reached. The 13 ¦ material was then dried and discharged.
14 ¦ Yield Sieve Analysis 1 4.55 9 -- ~1.-% +16 mesh 6.7 16 1~ 16-30 mesh 61.3 17 !1 -30 mesh 32.0%
18 li The fraction 16-30 mesh -- 2.79 kg -- was sintered as 19 1I described in Example 3.
ll Yield Sieve Analysis 21 ¦~ 2.63 kg -- 94.3% 16-20 mesh 4.7%
22 ¦1 20-40 mesh 91.5 23 ! ~40 mesh 3.8%
24 ! I EX~MPLE 5 11 5 0 kg of spray dried hydroxylapatite powder~
26 ! prepared as d~escribed in Example 2, was charged into a Glatt 27 I GPG 5-9 granulator.
28 ! 1. oo kg of polyvinylpyrrolidone (PVP) K29-32 was 29 1¦ dissolved in 4 liters of D.I. water. The rotor was turned on ~ at 400 rpm and the binder solution was fed in at lZ0 g/min 1~ -22-~ ~7~i7~;

1 ~initially and later at 49-60 g/min. Feeding was discontinued 2 when the desired particle size is reached. The material was 3 then dried and discharged.
4 ! Yield Sieve_Analysis I 4.65 kg -- 93.0% +16 mesh 16.3 6 ! 16-30 mesh 73.5 7 ¦ -30 mesh 10.2~
8 ~ The fraction 16-30 mesh -- 3.42 kg -- was sintered as 9 I described in Example 3.
Yield Sieve Analysis 11 3.23 kg -- 94.4% 16-20 mesh 4.1~
12 20-40 mesh 93.1%
13 -40 mesh 2.8 14 ~ EXAMPLE 6 1 4.0 kg of the spray dried hydroxylapatite was 16 ¦preagglomerated to the particle size 40-60 mesh.
17 ¦ 400 9 of the pregelatinized starch was dissolved in 18 ¦ 4600 g of D.I. water.
19 8.0 kg of the spray dried hydroxylapatite of particle size 20-40 microns was charged into the powder coating 21 injection port.
22 ~he rotor was turned on at 400 rpm speed, starch 23 solution was fed in at 80 g/min. and the powder injection was 24 set for 8.0 kg/hr. Agglomeration of particles 40-60 mesh and coating of this preagglomerate took place simultaneously. The 26 particle size 14-25 mesh was reached within 54 minutes. At 27 Ithis point the speed of the rotor was increased to 900 rpm 28 ¦ feed}ng of the powder and the starch was discontinued, heating 29 I was stopped and material was sprayed with D.I. water for 10 I minutes. Higher speed compacted the particles and increased ~ l 1 12~

1 ~ their ensity and the particle si7e shrunk to the desired 16-30 2 I mesh. The rotor speed was brought down to 400 rpm, water 3 ¦ spraying was discontinued and material was dried.
4 ¦ Yield Sieve Analvsis ¦ 11.34 kg -- 94.5% ~16 mesh 7.1%
6 ¦¦ 16-30 mesh 92.
3%
7 ¦ -30 mesh 0.6~
8 1 The fraction 16-30 mesh -- 10.47 kg -- w as sintered 9 1 as described in Example 3.
l~ Yield Sieve Analysis ~ 9.69 kg -- 92.5% 16-20 mesh 5.7%
12 ! 20-40 mesh 92.9 13 -40 mesh 1.4%

5.1 kg of the off size, granulated hydroxylapatite of 16 ~ particle size +16 mesh and -30 mesh was ground in the 17 ! hammermill to the particle size -80 mesh and charged into the 18 1 Glatt GRCG 5-9 granulator. This material was a leftover from 19 agglomeration as described in Example 4; and as such, it I contained starch used in the agglomeration.
21 400 9 of pregelatinized starch was dissolved in 4600g 22 of water.
23 Rotor was turned on at 400 rpm speed and starch 24 feeding started at 80 g/min. Agglomeration began within 10 `
minutes and the desired particle size 16-30 mesh was reached in 26 35 minutes. Faster response was due to the starch content in 27 the starting material. The material was dried and discharged.
28 ¦ Yie]d Sieve_Analysis 29 l 4.90 kg -- 96.1% +16 mesh 6.9%
j¦ 16-30 mesh 90.8 Il -24-1~ .

,. .1 12~9~L7S

1 ~ -30 mesh 2.3~
2 The fraction 16-30 mesh -- 4.45 kg -- was sintered as 3 described in Example 3.
4 Yield Sieve Analysis 4.13 kg -- ~2.8~ 16-20 mesh 6~1%

6 20-40 mesh 90.9%

7 -40 mesh 3.0%

9 5.0 kg of the spray dried hydroxylapatite and 400 grams of pregelatinized starch were charged into the Glatt GPCG
ll S-9 granulator.
l~ Rotor was turned on at 400 rpm speed and the 13 fluidized powder was sprayed with D.I. water at the rate of 80 14 g/min.-initially and at 40 g/min. rate later. Powder was lS gradually agglomerized and the spray of the water was 16 discontinued when the main fraction reached the size 16-30 17 mesh. Material was dried and discharged.
18 Yield Sieve Analysis l9 1 5.2 kg -- 96.3% +16 mesh 5.7%
16-30 mesh 90.9%
21 -30 mesh 3.4%
22 The fraction 16-30 mesh -- 4.73 kg -- was sintered as 23 described in Example 3.
24 Yield Sieve Analysis 4.38 kg -- 92.6% 16-20 mesh 2.8 26 20-40 mesh 93.7 27 -40 mesh 3.5%

29 5.0 kg of the agglomerated hydroxylapatite of the particle size 20-30 mesh was charged into the Glatt GPCG S-9 _ ~ 5_ 1 12~ .7~

1 ~I granu at~r with a Wurster column insert.
2 Sludge of the hydroxylapatite was prepared as 3 described in Example 2, redispersed in D.I~ water and 4 centrifuged again twice and diluted with D.I. water to contain ¦ 7% solids.
6 1 40 kg of this sludge was weighed; 300 9 of 7 ¦~ pregelatinized starch was addecl and dissolved in the sludge and 8 j this mixture was then sprayed on the fluidized bed of 9 ¦ granulated hydroxylapatite in the Wurster column at the flow ¦ rate 40-60 g/min. The product was dried, discharged and sieved.
12 li Yield Sieve Analysis 13 ll 7.72 kg -- 91.0~ +16 mesh 4.1%
14 ¦ 16-30 mesh 95.4 ¦ -30 mesh 0.5~
16 I The fraction 16-30 mesh -- 7.36 kg -- was sintered as 17 ¦¦ described in Example 3.
18 1! ~ield Sieve Analysis 19 li 6.92 kg -- 94.04% 16-20 mesh 11.1~
11 20-40 mesh 88.1%
21 !~ -80 mesh 0.8~
22 ¦ EXAMPLE 10 23 1 12-60 mesh hydroxylapatite was agglomerated with 24 polyvinyl pyrrolidone (PVP) binder generally following the agglomeration procedures set forth in the preceding Examples.
26 The binder was extracted as followso 20 g of the PVA
27 agglomerated hydroxylapatite was added to a solution of 2 ml 28 ¦1 isopropyl alcohol and 100 ml D.I. water heated to a boil, 29 1¦ allowed to cool for 2 hrs., decanted, dried at 110C to ¦ substantially constant weight and fired at 1200C for 2 hours.

1 i Yield Friability 2 9.8 g 6.2 4 ¦ The procedure of Example 9 was repeated except that S ¦the binder extraction step was carried out in 2 mls ammonium 6 hydroxide and 100 ml D.I~ water.
7 Yield E`riability 8 1 10.6 9 6.0 ! EXAMPLE 12 Four different batches of hydroxylapatite 11 agglomerated with polyvinylpyrolidone ~PVP) binder were 12 1 prepared generally following the procedure of Example 5.
13 The PVP binder was extràcted from a sample of each 14 batch of PVP agglomerated hydroxylapatite as follows:
109 of the PVP agglomerated hydroxylapatite was 16 added to 40 ml isopropyl alcohol (IPA), boiled, cooled for 2 17 ! hours, decanted, dried at 90C ~o substantially constant weight 18 ¦ and sintered at 1200C for 2 hrs.
19 BATCH NO. 1 2 3 4 Yield (after ext'n & drying) 8.2gm 7.7gm 7.9gm 7.&gm 21 j Yield (after sintering) 6.1gm 6.2gm 6.1gm 6.2gm 22 ¦Friability 5.3 6.1 6.5 6.4 23 ¦! EXAMPLE 13 24 ji Binder was extracted from three batches of PVP
¦agglomerated hydroxylapatite prepared generally in accordance 26 ¦ with the procedure of Example 10 as follows: :
27 ! About 1 liter of isopropyl alcohol was charged 28 ¦¦ in the extraction chamber of a Soxhlet-type extractor with 29 ~l about 1.5 kg of PVP agglomerated hydroxylapatite and refluxed 3~ 1¦ for 48 hours. The extracted material was removed from the i! l ll -27- ~

li .
!.

1 ~extractor and dried to constant weight. Samples periodically 2 Itaken from the extractor showed,~the following reduction in 3 !binder content:
4 I TIME (Hrs) 0 5 10 48 ¦1 % PVP (removed) 0 10 40 84 7 ¦ An extraction generally following the procedure of 8 IExample 11 was repeated and yielded the following result:
9 ¦ TIME (Hrs) 0 2 24 49 73 1l% PVP (pr~sent) 20 12 15 13 0.2 11 , EXAI~PLE 15 12 ! Batches of hydroxylapatite agglomerated with 13 ipolyvinyl alcohol, polyvinylpyrolidone, hydroxypropyl 14 !cellulose, and starch binders were prepared qenerally following j¦the procedures set forth in the preceding Examples.
16 ll Samples from each batch of the hydroxylapatite 17 1 agglomerates were placed in an oven having an oxygen atmosphere 18 j and heated at the rate of 20C per min. to 500C each producing 19 ¦ white material which produced acceptable ceramics, i.e.
Ij Friability greater than about 3.0, and an unchanged X-ray 21 !i diffraction pattern (approximately 100~ hydroxylapatite).

22 11 .~.
23 i!
24 ll r 27 ;
29 11 l Il .

.
!.1 .... ~ _

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A method for preparing sintered ceramic particles for use as a human implant material, the method comprising:
a) agglomerating together dry particles of a calcium phosphate compound in the size range of 1-75 microns with a binding agent to provide sinterable agglomerates having a size range of about 10-80 mesh;
b) extracting an amount of binder from said agglomerates sufficient to provide sintered agglomerates which do not exhibit carbonized binder discoloration when said agglomerates are subjected to sintered temperatures;
and c) subsequently sintering said agglomerates to provide said ceramic particles.

2. The method according to Claim 1 wherein said extraction step comprises heating said agglomerates to a first temperature less than their sintering temperature to extract said binding agent.

3. The method according to Claim 2 wherein said heating to said first temperature is conducted in an oxygen enriched atmosphere.

4. The method according to Claim 3 wherein said heating to a first temperature is at the rate of about 20°C/minute and said first temperature is about 500°C.

5. The method according to Claim 1 wherein said extraction step comprises extracting said binder from said agglomerates with a liquid and separating the agglomerate from the liquid before said sintering step.

6. The method according to Claim 5 wherein said binding agent is selected from the group consisting of starch, pre-gelatinized starch, polyvinyl alcohol, polyvinylpyrrolidone, and hydroxypropyl cellulose.

7. The method according to Claim 6 wherein said liquid is selected from the group consisting of methanol, isopropyl alcohol, methylene dichloride and aqueous solutions thereof.

8. The method according to Claim 1, 2, 3, 4, 5, 6 or 7 wherein said calcium phosphate compound is tricalcium phosphate, hydroxylapatite or a mixture thereof.

9. The method according to Claim 8 further comprising the step of preparing said sinterable particles by spray-drying an aqueous suspension of said sinterable particles to provide a fine dry powder comprised of said sinterable particles.

10. The method according to Claim 8 wherein said sinterable particles are comprised of hydroxylapatite and wherein said agglomerate is substantially spheroidal in shape.

11. The method according to Claim 10 wherein said agglomerate is prepared by applying said binding agent to a rotating fluidized bed of said sinterable particles.

12. The method according to Claim 11 wherein a major portion of said agglomerate is in about the 16 to 30 mesh range.

13. The method according to Claim 1 wherein said dry particles of said calcium phosphate compound are prepared by diluting an aqueous gel of hydroxylapatite with water and then spray drying the diluted gel to provide a dry powder of porous sinterable hydroxylapatite particles in the size range of about 1 to about 75 microns; said agglomerates are prepared by applying a binding agent to a rotating fluidized bed of said dry hydroxylapatite particles, to provide substantially spheroidal particulate agglomerates in the size range of about 10 to about 80 mesh; said agglomerates are heated to an elevated temperature below about 700°C to substantially eliminate said binding agent and to provide an agglomerate of adherent hydroxylapatite particles which is substantially free of residue of said binding agent, and said agglomerate is sintered at a temperature of about 1000°C to about 1300°C for about 1 to about 3 hours to provide ceramic hydroxylapatite particles which are substantially spheroidal in shape, and include a network of micropores extending throughout said ceramic particles.

14. Sintered ceramic particles prepared by the process of Claim 1.

15. Sintered ceramic particles prepared by the process of Claim 13.