Note: Descriptions are shown in the official language in which they were submitted.
;S~2
The present invention relates to ceramics, parti-
cularly for use in dentistry and orthopedics,
- Much current den~al research is focused on the
preparation of materials which can be used as a substitute
for tooth and bone, as a dental restorative material for
fillings, caps and crowns and as a prosthetic filling mate-
rial for bone. Den~al research also is directed to prevent-
ing the formation of dental plaque, the putative agent of
both dental caries and periodontal disease~
Currently used filler materials for dental restor-
ative compositions such as quartz, alumina, silicates, glass
beads, etc., bear little chemical or physical resemblance
to tooth enamel. ~ particular deficiency of these materials
lies in the incompatibility of the linear coefficients of
expansion of filler material and tooth which can eventually
result in marginal leakaye and new caries formation. The
dental profession, therefore, has lon~ desired a dental
filling composition with physical properties which closely
conform to those of na~ural tooth structure.
2~ Furthermore, in the field of surgical prosthetic
ma~erials, which is currently dominated by high-strength,
non-corrosive alloys, there is a recognized need for a mate
rial which more closely resembles biological hard tissue as
the problems of tissue acceptance and adherence have not as
yet been comple~ely resolved ~Hul~ert, et al., Materials
`~
Science Research 5, 417 (1971)].
In research directed to ~he discovery of effective
anti-plaque chemotherapeutic agents there is need for a
standard test material having a tooth-like surface with re-
spect to both plaque formation and substantiveness of chem-
ical agents. Although natural teeth have been used for this
purpose, these have the drawbacks of being highly variable,
relatively unavailable in large numbers, and require elabor-
ate cleaning before use. Consequently there are used other
materials upon which dental plaque will accumulate such as
powdered hydroxylapatite, acrylic tee~h, glass and wire.
Although perhaps adequate for studying plaque formation as
such, these materials bear little resemblance to the natural
tooth surface and are therefore not completely suitable for
use in flnding effective anti-plaque agents. For example,
it is known that chemicals which inhibit plaque formation on
- teeth do not necessarily do so on glass and wire [Turesky
et al., J. Periodontology 43, 263 (1972)]. There is a need
then for an inexpensive, readily available material which is
chemically similar to tooth enamel, hard, dense, and highly
polished.
' Cal0(PO4~6~OH)2~ also known as
basic calcium orthophospha~e, the mineral phase of tooth and
bone, has been suggested as suited to the various purposes
ou~lined above, and in fact United States Patent 2,508,816
discloses a method for obtaining the hydroxylapatite of tooth
enamel and its use in admixture with a synthetic resin as a
prosthetic tooth composition. This procedure is lengthy and
laborious and limited to producing finely divided hydroxylapa-
tite. Moreover, the method is of course dependent on the
--3
6S~Z
availability of a supply of natural teeth.
Kutty [Indian J. Chem. 11, 695 (1973)] disclosed
mixtures of hydroxylapatite and whitlockite produced by the
decomposition of powdered hydroxylapatite at various tempera-
tures.
Bett, et al., [J. Amer. Chem. Soc~ 89, 5535 (1967)]
described the preparation of particulate hydroxylapatite with
stoichiometry varying from Ca/P = 1.67 to 1.57, The mate-
rials so-produced contained large intercrystalline pores,
It was also reported that upon heating up to 1000C. the
calcium-deficient hydroxylapatites underwent partial trans-
formation to the whitlockite phase.
United States Patent 3,787,900 discloses a bone
and tooth prosthetic material comprising a refractory com-
pound and a calcium phosphate compound, e.g,, whitlockite,
Several attempts have been made to provide a hard,
strong macroform of hydroxylapatite. However, none of the
previously known forms of hydroxylapatite has provèn fully
satisfactory. Thus, Roy and Linnehan [Nature, 247, 220
(1974)~ described ar. elaborate hydrothermal exchange process
whereby the skeletal calcium carbonate of marine coral was
converted to hydroxylapatite. The material so produced
necsssarily retained the high porosity characteristic of
the coral structure and moreover had a relatively low tensile
strength of about 270-470 psi, a serious disadvantage in a
prosthetic materialO
Monroe, et al. [Journal of Dental Research 50,
860 (1971~ reported the preparation of a ceramic material
by sintering compressed tablets of hydroxylapatite. The
material so produced was actually a mixture of hydroxylapatite
--4--
~6S8Z
and approximately 30 per cent ~-whitlockite, which is
Ca3~PO4)2 or tricalcium phosphate, as an ordered mosaic array
of polyhedral crystallites, and appeared to have too much
porosity to make it suitable for use in a dental material.
Rao and Boehm [Journal of Dental Research 53, 1351
(1974)] disclosed a polycrystalline form of hydroxylapatite
prepared by isostatically pressing powdered hydroxylapatite in
a mold and isothermally sintering the molded form. The result-
ing ceramic was porous and had a maximum compression strength
of approximately 17,000 psi.
Bhaskar, et al., [Oral Surgery 32, 336 ~1971)] de-
scribed the use of a biodeyradable calcium phosphate ceramic
material to fill bone defects. The material is highly porous,
is resorbed from the implant site and lacks the strength of a
metal or nondegradable ceramic implant.
In accordance with the present invention there is
provided a process for preparing a polycrystalline, sintered
ceramic in macroform which comprises reacting calcium ion
with phosphate ion in aqueous medium and at pH of about 10-12
to produce a gelatinous precipitate of a phosphate of calcium
having a molar ratio of calcium to phosphorus between the
approximate molar ratio of calcium to phosphorus in hydroxyl-
apatite and that in whitlockite, separating said precipitate
from solution, heating a cohesive ~elatinous mass of said pre-
cipi~ate up to a temperature of at least 1000~C. but belowthat at which appreciable decomposition of hydroxylapatite
occurs, and maintaining said temperature for sufficient t`ime
to effect the sintering and substantially maximum densifica-
tion of the resulting product.
s~ ~
The process of the present lnvention
proYides a polycry~talline, isotropic sintered ceramic
having clea~ag along smooth curved planes compr;sing
either substantially p~re hydroxylapatite or biphasic
hydroxylapatite-whitlockite. According to
one aspect of the present invention said product is
a translucent, isotropic, polycrystalline, sintered
ceramic comprising substantially pure hydroxyl- ;
apat;te having an average crystallite size in tne
approximate range 0.2 to 3 microns, said. ceramic having
a densit~y in the approximate range 3.10 to 3.14 g/cm3,
having suhstantially no pores~ and havins cleavage along
smooth curved p'anes. in accordance with a second
aspect of the present invention said product is a
strong, hard, dense, ;sotropic, polycrystalline sintered
biphasic ceramic comprisirlg as one phase from a~out
14 to 9~% by weight of hydroxylapatite and as a second
phase from about 2 to 86% ~y weight of whitlockite,
said ceramic ha~Jing clea~age along smooth curved planes.
The ceramic o-f the one aspect of the present
inventioll
; ~5a
~0~6S~3~
comprising substantially pure hydroxylapatite is hard,
dense, and takes a high polish. Chemically is it very similar
to tooth enamel. Moreover, this new material can be prepared
in a relatively simple manner from inexpen~ive starting
materials and is obtained in uniform quality, thereby avoid-
ing the undesirable variability inherent in natural teeth.
The incorporation of the novel ceramic form of
hydroxylapatite in dental restorative compositions provides
a dense filler material which has a coefficient of expansion
virtually identical to ~hat of natural tooth enamel.
The dental and surgical implant material made
available by the instant invention is hard, strong, and c~m-
pletely bio-compatible, and can be fabricated in any desired
shape without the need for high pressure or other elaborate
techniques. Moreover, as described in detail hereinbelow,
any desired degree of porosity can be imparted to such mate-
rial, thereby permitting tissue ingrowth.
As will be apparent, the chax~cteristics of the new
article of manufacture herein described and claimed make it
ideally ~uited to making disc~, plates~ rods, etc. for use
in testing dental anti-plaque agents.
The novel biphasic ceramic material comprising
hydroxylapatite and whitlocki~e i8 hard, dense, non-porous,
bio-compatible, easily fabricated in any de~ired shape or
form, and by virtue of the known resorbable nature of
whitlockite, is useful a~ a strong, partially rescrbable
~urgical implant material.
~hile a certain degree of porosity in surgical im-
--6--
S~2
plant materials may be advantageous in permitting circula-
tion of body fluids and tlssue ingrowth, this same porosity
necessarily reduces the mechanical strength of the implant.
The biphasic ceramic afforded by this invention, although
dense, mechanically strong and substantially non-porous, may
nonetheless permit circulation of body fluids and tissue in-
growth because the whitlockite phase contained therein is
slowly resorbed from the implant and replaced by natural
biological hard tissue.
U~ jA~ pV~
The novel physical form of~hydroxyla'patite, which
is distinguished from the biologlcal and geological forms
and from all previously known synthe~ic forms as hereinafter
indicated, consists of a strcng, hard, de~se, white, trans-
lucent isotropic, polycrystalline sintered ceramic material
comprising su~stantially pure hydroxylapatite having an aver-
age crystallite size in the approximate range 0.2 to 3 microns,
a density in the approximate range 3~10 to 3.14 g/cm3, and
being further characterized by the absence of pores and by
cleavage along smooth curved planes. Moreover, as ordinarily
produced, the above ~escribed material has a compression
strength in the approximate range 35,~00 to 125,000 psi, a
tensile strength in the approximate range 3,000 to 30,000 psi,
a linear thermal coefficient of expansion in the approximate
range lO to 12 ppm per degree Centrigrade, a Xnoop hardness
in the approximate range 470 to 500 and a modulus of elas-
ticity of approximately 6 x 106 psi, and is non-bixefringent
under polarized light~ The initial evaluation of the novel
hydroxylapatite ceramic indicated that it was a strong, hard,
dense, white, translucent ceramic comprising substantially
pure microcrystalline hydroxylapatite in a random, isotropic
--7--
8Z
array and having a compression strength in the approximate
range 35,000 to 75,000 psi, a tensile strength in the
approximate range 3,000 to 50,000 psi, a linear thermal
coefficient of expansion in the approximate range 10 to 12
ppm per degree Centigrade, a Knoop hardness in the approx-
imate range 470 to 500 and a modulus of elasticity of approx-
imately 6 x 106 psi, and ~eing characterized by cleavage along
smooth curved planes, and by the absence of birefringence
under polarized light.
The term dense as used herein designates a highly
compac~ arrangement of particles substantially lacking spaces
or unfilled intervals therebetween.
In contrast to the above-described form of
hydroxylapatite, geological hy~roxylapatite and synthetic
hydroxylapatite prepared by a hydrothermal process are macro-
crystalline, fracture along flat planes, and are birefringent.
Biological hydroxylapatite is distinguished by generally con-
taining significant amounts of carbonate ion in the apatite
lattice and in its purest state, i.e., in tooth enamel, by
being anisotropically arranged in coiled radiating rods, so
that it fractures in straight lines along the interface of
these enamel rods and has a comparatively low tensile
streng~h of 1500 psi.
In addition to the above-described properties of
the novel ceramic form of hydroxylapati~e provided by this
invention this material is also completely bio-compatible
and therefore eminently suita~le as a dental and surgical
prosthetic material. Thus~ the ceramic of this invention
can be cast or machined into dental crowns, artificial teeth,
bone and joint prostheses, cannulae, anchoring devices for
-8-
;58;Z
artificial limbs which can be attached to bone and protrude
through the skin, and test surfaces for the study of dental
plaque, caries formation, arthritis and other diseases which
may affect teeth and bone. Suitably milled, the novel
ceramic of this invention can be used as synthetic canncellus
bone to repair bone defects, as an abrasive, and composited
with standard resins as a dental restorative composition as
described hereinbelow.
As a test surface for the evaluation of dental
plaque-inhibiting agents the ceramic of this invention can
be fabricated into bodies of any suitable size and shape~
preferably of a size and shape which can be easily inserted
into a standard test tube. This is conveniently accomplished
by cutting or machining large plate-like pieces of dried
filter cake to an appropriate size and then sintering~ The
sintered products are highly polished using standard lapidary
techniques and the resulting bodies are then used as sub-
strates in evaluating dental plaque-inhibiting agents accord-
ing ~o the procedures described by Turesky, et al., sup~.
After use the ceramic bodies are simply re-polished to pro-
vide a new test surface.
As ordinarily produced the ceramic of this inven-
tion is not only dense but also non-porous, and whereas a
non-porous material is essential for dental applications,
a certain degree of porosi~y in implant devices may be ad-
vantageous in permitting circulation of body fluids and
tissue ingrowthO Varying degrees of porosity can be impart-
ed to the instant ceramic in a manner similar to that describ-
ed by Monroe, et al., supra. Thus, organic materials such as
s~arch, cellulose, cotton, or collagen in amounts ranging
~g _
8Z
from about 5 to 25 per cent by weight are admixed with the
gelatinous precipitate of hydroxylapatite. During the sub-
sequent sintering process the organic materials are burned
out thereby creating holes and channels in the otherwise non-
porous ceramic product. Alternatively, porosity can be pro-
duced mechanically by drilling or machining holes and open-
ings in the non-porous ceramic.
In such manner an artificial tooth composed of the
ceramic of this aspect of the invention can be made porous
at the point of implantation while the exposed tooth surface
remains non-porous. Implantation can be accomplished as re-
ported by Hodosh, et al., Journal of the American Dental
Associa~ion 70, 362 (1965~ Alternatively the ceramic pro-
vided by the invention can be composited with a polymeriz-
able or polymerized ~onding material as described herein-
below and the resulting composition used as a coating for
metal implants as described in United States Patent 3,6~9,867,
issued October 5, 1971.
The second aspect of this invention mentioned above
resides in a strong, hard, dense, white, isotropic, poly-
crystalline sintered ceramic product comprising as one phase
~rom about 14 to 98~ by weight of hydroxylapatite and as a
second phase ~rom about 2 to 8~ by weight of whitlockite and
being characterized by the absence of pores and by cleavage
along smooth curved planes.
Whitloakite, also known as tricalcium phosphate,
is a mineral having the chemical formula Ca3(P04)2 and which
may exist in either an ~ or ~ crystalline phase. The term
whitlockite as used herein designates either the ~ or the
phase or a mixture of the two phases.
--10--
6S82
The biphasic ceramic of this invention remains
a non-porous polycrystalline material irrespective of the
relative concentrations of hydroxylapatite and whitlockite
contained therein. However, it will be appreciated that
hydroxylapatite and whltlockite have different physical
properties, and therefore the physical properties, e.g.,
density and op~ical properties of the ~iphasic ceramic will
depend on the relative amounts of hydroxylapatite and whit-
lockite present therein. For example, the theoretical
density of whitlockite is less than that o~ hydroxylapatite
and accordingly the observed density of a sample of biphasic
ceramic containing about 40% hydroxylapatite and 60% whit-
lockite was 2.98 g/cm3 compared to a density of 3.10 g/cm3
for a sample of hydroxylapatite ceramic.
The above-described biphasic ceramic is also bio-
compatible and therefore suitable as a surgical prosthetic
material. Thus, this material can be cast or machined into
~one and joint prostheses or into any shape suitable for
filling a void or defect in a bone. The whitlockite contain-
ed in a prosthetic article fabrica~ed from this biphasic
c~ramic will eventually be resorbed and replaced by the in-
growth of natural biological hard tissue. Of course, the
extent of tissue ingrowth will depend on the amount of re-
sorbable whitlockite contained in ~he ceramic,
As ordinarlly produced the biphasic ceramic of
this invention is non-porous. However, if desired, varying
degrees of porosity can be imported to the ceramic as describ-
ed hereinabove for khe novel ceramic form o~ hydroxylapatite.
The biphasic ceramic may also be rendered acid
3G resistant by fluoridation as described hereinbelow for
~65~
ceramic hydroxylapatite.
The above-described novel ceramic form of hydroxyl-
apatite can be prepared by precipitating from aqueous medium
at a pH of about 10-12 hydroxylapatite having a molar ratio
of calcium to phosphorus in the approximate ranga 1.62-1.72,
separating the precipitated hydroxylapatite from the solu-
tion, and heating~the hydroxylapatite thus obtained at a
temperature and for a time sufficient to effect the sinter-
ing and maximum densification of said hydroxylapatite with
essentially no decomposition thereof.
Thus, hydroxylapatite is precipitated from aqueous
medium by reacting calcium ion with phosphate ion at a pH
of about 10-12. ~ny calci~- or phosphate-containing com-
pounds which provide calcium and phosphate ions in aqueous
medium are suitable provided that the respective counter ions
of said compounds are easily separated from the hydroxylapatite
product, are not themselves incorporated in the hydroxyl-
apatite lattice, or othexwise interfere with precipitation
or isola~ion of substantially pure hydroxylapatite. Compounds
which provide calcium ion are, for example calcium nitrate,
calcium hydroxide, calci~n carbonate and the like. Phosphate
ion may be provided by diammonium hydrogen phosphate,
ammonium phosphate, phosphoric acid and the like~ In the
present method calcium nitrate and diammonium hydrogen phos-
phate are the preferred sources of calcium and phosphate ions,
respectively.
The preparation of the instantly clàimed novel form
of hydroxylapatite is conveniently carried out as follows:
Firs~, calcium nitrate and diammonium hydrogen phosphate in
a molar ratio of 1.67 to 1 are interacted in aqueous solution
-12-
~65~2
a a pH of about 10-12 to produce a gelatinous precipitate
of hydroxylapatite. The procedure described by Hayek, et al,,
Inorganic Syntheses 7 63 (1963) is satisfactory for this
purpose. The gelatinous suspension of hydroxylapatite thus
obtained is then allowed to remain in contact with the
original solution for a ~ime sufficient to allow the calcium
to phosphorous ratio of ~he suspended hydroxylapatite to
reach a value of about 1.62-1.72. This is conveniently
accomplished either by stirring the suspension at room
temperature ~or a period of not less than 24 hours, or by
boiling the suspension for a period of 10 to 90 minutes,
or by a combination of boiling followed by standing at room
temperature. Pxeferably the suspension is boiled for 10
minutes and thPn allowed to stand at room temperature for
15-20 hours. The hydroxylapatite is then separatéd from
the solution by sultable means, for example by centrifugation
and vacuum filtratlon. The gelatinous product thus collected
contains a large amount of occluded water, much of which can
be removed by pressingO If desired, the resulting wet clay-
like material can be cut or shaped into a convenient form,
or, alternatively, cast in a suitable mold. It should be
noted that ordinarily a shrinkage of approximately 25 per
cent occurs when the wet hydroxylapatite is dried and a
further shrinkage of about 25 per cent takes place during
the sintering hereinafter described. This should of course
be taken into account when shaping or molding the material~
The wet product may ~e slowly heated up to the sintering
/~o o~
B~ temp~rature of ~05~DC. to 1250C. at which point all remain-
ing water will have been driven off. Maintaining the temp-
/00 0 ~G
erature at }~ ~. to 1250C. for approximately 20 minutes
-13-
5~
to 3 hours will then effect the sintering and maximum densi-
fication ~f the product. Ordinarily it is preferred to iso-
late the dried produc~ prior to sintering. Thus, the wet
product may be dried at about 90~C. to 900C. for approxim-
ately 3 to 24 hours or until the water content thereof hasbeen reduced to 0 to about 2 per cent. It is generally pre-
ferred to use drying conditions of approximately 90C. to
95C. for abcut 15 hours or until the water content has
been reduced to about 1 to 2 per cent. The hydroxylapatite
ob~ained in this manner is britt1e and porous, but has con-
siderable mechanical strength. Some separation or cracking
of the clay-like ma~erial may occur on drying especially if
a thick filter cake is used. However, pieces as large as
100 cm2 and 3 mm. in thlckness are readily obtained. Separa-
tion or cracking during drying can be minimized or preventedby adding to the suspension of freshly precipitated hydroxyl-
apatite about 0.4 to 0.6 per cenk by weight of an organic
binder such as collagen, powdered cellulose or cotton, about
0.5 per cent of collagen being preferred. The organic binder
is volatilized during subsequent sintering and physical
characteristics of the ceramic product appear substantially
unchangsd from those of the product produced in the absence
of such a binder. Of course, ~he use of substantially larger
amounts of organic binder will result in a porous ceramic
pxoduct as described above. Other conventional organic and
inorganic binders known in the ceramics art can also be used.
It is usually convenient at this stage to further
cut or shape the dried hydroxylapatite into roughly the form
desired as the end product, taking into account the shrinkage
mentioned above which occurs on sintering.
-14-
658%
The bodie~ of hydroxylapatite prior to sinterin~
should be uniform and free oE defects. The presence of
cracks or fissures can cause the pieces to fracture during
the sintering process~ The products are then sintered at
/~ ~ O
B 5 about ~ 4~. to 1250C. for approximately 20 minutes to
three hours, the temperatures and times being inv~rsely
related. Sintering is preferably effected at 1100C. to
1200C. for approximately 0.5 to 1 hour. The hard, dense
ceramic articles so produced can then be polished or machined
using conventional techniques.
It is critical, in the above process, to prepare
the hydroxylapatite as a gelatinous precipitate from aqueous
solution for it is only in ~his cohesive gelatinous state
that hydroxylapatite can be shaped or molded and then dried
and sintered to produce the ceramic in macroform. Dry
particulate or granular hydroxylapati~e cannot be reconsti-
tuted into ~his cohesive gelatinous state. If, for example,
powdered hydroxylapatite is suspended in water and filtered
th~re i5 o~tained a non-cohesive, particulate filter cake
which qimply dries and crumbles and cannot be shaped, molded
or converted into a macroform of the ceramic. Moreover,
although powdered hydroxylapatite can be mechanically com-
pxessed into a shaped body, such as a tablet, when sintered
according to the method of this invention the product obtain-
ed is highly porous and does not fracture along smooth
planes but simply shatters into rough pieces~
Although the formation of hydroxylapatite in
aqueous medium is a complex and incompletely understood pro-
cess, it is generally believed that calcium and phosphate
ions initially combine to form a calcium-deficient hydroxyl-
-15-
~IJ2~S8~:
apatite having a calcium-to-phosphorus ratio of about 1.5.
In the presence of calcium ion, this species thsn undergoes
slow transformation ~o hydroxylapatite with a calcium-to-
phosphorus ratio of 1.67. ~Eanes et al., Nature 208, 365
(1965) and ~ett et al., J. Amer. Chem. Soc. 89, 5535 (1967).
Thusj in order to obtain a ceramic comprising substantially
pure hydroxylapatite it is imperative in the process o~ this
invention that the initial gelatinous precipitate of hydroxyl-
apatite be allowed to remain in contact with the original
solution for a time sufficient to allow the calcium to
phosphorus ratio thereof to reach a value of about l.h2 to
1.72. 5ubstantial deviation from this range results in a
less translucent ceramic product. For example, if hydroxyl-
apatite is precipitated at room temperature and collected
within 2 hours following precipitation the calcium to phos-
phorus ratio thereof is found to ~e about 1.5S-1.57 and the
ceramic ultimately produced therefrom is opaque and found by
X-ray diffraction ~o be a mixture compri~ing hydroxylapatite
; and whitlockite. In fact, as described more particularly
hereinbelow, material having a calcium to phosphorus ratio
of about 1.44~1.60 i~ useful in ~he preparation of the bi-
phasic ceramic described hereinabove. Thus, while the pro-
cess claimed herein affords a translucent ceramic comprising
sub ~antially pure hydroxylapatite, in view of the incom-
; 25 pletely understood mode of formation of hydroxylapatite in
aqueous medium it may be advantageous to monitor the hydroxyl- --
apatite formation in oxder to ascertain that the desired
calcium to phosphorus stoichiometry has been achieved and
that the product when ~intered will comprise substantially
pure hydroxylapatite. This is conveniently accomplished by
-16-
~` lQ~58~
removing an aliquot of the hydroxylapatite suspension, sepa-
rating the product, drying and sintering a~ de~cribed herein-
above, and subjscting the ceramic so-produced to elemental
and X-ray analysis.
The temperature and duration of sintering are also
critical to the claimed process. Thus, unsintered
hydroxylapatite having the desired ealcium-to-phosphorus of
1.62-1.72 can be converted to the ceramic of this invention
by heating at a temperature of at least about 1000C.
At 1000C. complete sintering and maximum densification
may require 2-3 hours while at 1200Cr the process may
be complete in 20~30 minutes. It is preferred to effect
sintering at a temperature of approximately 1100C~ for about
one hour. A temperature substantially below 1000C. will
result in incomplete sintering irrespective of the length of
heating whereas heating above 1250C. for more than ~ne hour
will result in partial decomposition of hydroxylapatite to
whitlockite.
The above-described biphasic ceramic comprising one
phase of hydroxylapatite and a second phase of whitlockite
can be prepared by precipitating from aqueous solution at a
pH of about 10-12 a calcium phosphate compound having a molar
ratio of calcium to phosphorus in the approximate range
1.44-1.60, prPferably 1.46-1.57, separating the precipitate
~5 from the solukion and heating the solid thus obtained at a
temperature and for a time ~ufficient to effect the sinter-
ing and maximum den~ification thereof.
The calcium phosphate compound having the requixed
~toichiometry, viz, Ca/P - 1.44-1,60 is obtained by inter-
acting calcium ion with pho~phate ion in aqueous medium at
-17-
;8~
pH 10-12, employing the same sources of calcium and phosphate
ions described hereinabove for the preparation of single
phase hydroxylapatite. Calcium nitrate and diammonium hydro-
gen phosphate are the preferred reagents.
Thus, the biphasic ceramic may be prepared by
interactiny calcium nitrate and diammonium hydrogen phos-
phate in a molar ratio o 1.67 to 1, i.e,, as described
hereinabove for the preparation of single phase ceramic
; hydroxylapatite provided that the initial gelatinous precipi-
tate is not heated and is allowed to remain in contact with
; the original solution for a period not to exceed about 4
houxs or alternatively that the molar ratio of calcium to
phosphorus of the precipitate not be allowed to exceed a
value of about 1~60.
As descri~ed hereinabove for the preparation of
single phase ceramic hydroxylapatite, the calcium phosphate
precipitate is separated from the solution, washed, optionally
haped or molded into a convenien~ form, and if desired dried
and isolated prior to sintering.
The suspension of freshly precipitated calcium phos-
phate may also be treated with organic binders or fluoride
ion as described hereinabove for single phase hydroxylapatite.
~ /oo~ ~
- D Sintering is effected by heating at about ~05~~_
to 1350~C. for approximately 20 minutes to 3 hours.
The amount of whitlockite contained in the ceramic
so-produced will depend on the time at which the precipitate
is separated from the original solution and may range from
about 2 to 83%. Thus, when the product is isolated 5 minutes
following precipitation, the calcium to phosphorus ratio
thereof is 1.55 and the ceramic ultimately produced therefrom
-1~
1~6~82
contains about 83% whitlockite. If the product is isolated
2 hours after precipitation the calcium to phosphorus ratio
thereof is 1.57 and the resulting ceramic contains a~out 61%
whitlockite. Isolation of the product 4.5 hours following
S precipitation ultimately affords a ceramic containing an
estimated 2% whitlockite, an amount barely detectable by
X-ray diffraction which has a minimum concentration sensi-
tivi y of 2-3%. Of course, i the product is allowed to re-
main in contact with the original solution beyond about 7
hours the ceramic ultimately obtained is substantially single
; phase hydroxylapatite.
Al~ernatively, the biphasic ceramic afforded by
the present invention may be prepared by reacting calcium
ion with phosphate ion in an approximate molar ratio of
1.50-1.60 to 1. In this way the molar ratio of calcium to
phosphorus in the calcium phosphate precipitate cannot
exceed a value of about 1,60 irrespective of the length of
time said precipitate remains in contact with the original
solution~
Thus, the preparation of the instantly claimed bi-
phasic ceramic is conveniently carried out as described
hereinabove for the preparation of single phase ceramic
hydroxylapa~ite with the exception that the reactants, viz.
`i calcium nitrate and diammonium hydrogen phosphate are inter-'~ 25 acted in an approximate molar ratio of 1.50-1.60 to 1 to
; produce ceramics comprising about 30-50% hydroxylapatite and about 50-70% whitlockite.
The ceramic may ~e further enriched in the whit-
lockite phase by com~ining the features of the two preceding
procedures, i.e., by interacting calcium ion with phosphate
--19--
~0~6S~
ion in an approximate molar ratio of 1.50-1.60 to 1 and iso-
lating the precipitated calcium phosphate compound within a
short time, preferably about 5 minutes to 4 hours, following
precipitation. Ceramics so-produced comprise about 10-30
hydroxylapatite and 70-90% whitlockite.
Hydroxylapatite is known tc undergo decomposition
to produce whitlockite at about 1250C. and it will there-
for be appreciated ~hat prolonged heating of the single phase
ceramic hydroxylapatite of this invention at temperatures
of about 1250~C. or higher will result in partial decomposi-
tion of said hydroxylapatite ~o whitlockite thereby provid-
ing yet another method of producing the instantly claimed
biphasic ceramic.
The invention also deals with a dental restorative
composition comprising a blend of the ceramic hydroxylapatite
of this invention and a polymerizable or polymerized bonding
material which is compatib~e with the conditions of the oral
cavity. The dental restorative composition of this invention
comprises from a~out 10-90 pex cent, preferably 60 to 80 per
cent, by weight of finely divided ceramic hydroxylapatite,
the remainder of said composition, from about 10-90 per cent
by weight, comprising a dentally acceptable polymerizable or
polymerized bondiny material together with known appropriate
polymerization catalysts, such as, aliphatic ketone peroxides,
benzoyl peroxide, etc., reackive diluents such as di-, tri-
and tetraethylene glycol dimethacrylate, hardeners such as
N-3-oxohydrocarbon-substituted acrylamides as described in
United States Patent 3,277,056, issued October 4, 1966, pro-
moters or accelerators such as metal acetyl acetonates,
tertiary amines, e.g., N,N-bis-~2-hydroxyethyl)-~-toludine,
~20-
58~
et~., or cross-linking agents such as zinc oxide, etc.,
which are present in an amount ranging from about 0.01 to
45 per cent by weight of the total composition. Although
not essential, a surface-active comonomer or keying agent
such as the reaction product of N-phenyl glycine and glycidyl
methacrylate as described in United States Patent 3,200,142,
issued August 10, 1965, methacryloxypropyltrimethoxysilane,
3,4-epoxycyclohexylethyltrimethoxysilane, vinyltrichloro-
silane, etc., may he added to said composition in an amount
ranging from 0.05 to 10 per cent by weight of the total
composition. The bonding or keying agent promotes bonding
o~ the ceramic material to the resin and of the dental
filling composition to the natural ~ooth. Thus, ceramic
hydroxylapa~ite provided by this invention is comminuted
to a suitable particle size of from about 5 to 100 microns
using conventional milling techniyues and then blended with
an appropriate amount of a standard resin known in the dental
; restorative art such as hydroxyle~hyl methacrylate, poly-
methyl methacrylate, polyacrylic acid, propylena glycol
fumarate ph~halate unsaturated polyesters such as sold by
Allied Chemical Co. 23 LS8275 and by Pittsburgh Plate Glass
as Selectron 580001, styrene modified unsaturated polyesters
such as Glidden Glidpol*1008, G-136 and 4CS50, epoxy resins
such as Ciba Aral~ite*Ç020, Union Carbide ERL2774 and the
bisacrylate monomer prepared from glycidyl methacrylate and
bisphenol A shown in United States Patent 3,066,112, issued
Nov. 27, 1962. The resin may comprise a single monomer or
- a mixture of two or more comonomers. Additives such as
dyes, inorganic pigments and fluorescent agents may be
optionally added to the above composition according to the
*-Registered Trade Mark -21-
~3
principles known ln the art concerning these materials.It is convenient to blend the resin, ceramic hydroxylapatite
and optional ingredients such as silane bonding agents, dyes,
inorganiC pigments or fluorescent agents prior to the addi-
tion of the catalyst, hardener, cross-linking agent, pro-
moter or accelerator. However, the order in which the in-
gredients are mixed is not critical and said ingredients
may be blended simultaneously. Utilizing conventional
techniques the composition thus produced can be used as a
dental filling material, a dental cement, a cavity liner,
a pulp capping agent or the composition can be cast in a
suitable mold to produce an artificial tooth or set o teeth.
It is of course highly advantageous that material
used in the oral cavity be caries resistant. This object
is readily achieved in the practice of the present invention
by adding from about 0.01 to l per cent fluoride ion such as
ammonium or stannous fluoride to the suspension of freshly
precipitated hydroxylapatite. The ceramic produced by sinter-
ing of the resulting product is highly resistant to attack
by lactic, acetic ox citric acidJ a standard ln vitro method
of detexmining caries resistance, Alternatively, resistance
to caries can be imparted to the finished ceramic by exposing
the same to a 0.5 to 5 per cent aqueous solution of sodium
fluoride for about 12 hours to five days, Preferably, the
ceramic body is allowed to stand in about 5 per cent a~ueous
sodium fluoride for appxoximately 4 days.
It will of course be appreciated by those skilled
in the ceramics art that in addition to organic and inorganic
binders and fluoride ion the ceramic materials provided by
the present invention may also contain small amounts of other
-22-
582
elements which although not changing the essential nAture
of the ceramic products may impart useful characteristics
thereto. For example, it is known that barium and stron-
tium will incorporate into the apatite crystal lattice and
that these elements are considerably more opaque to X-rays
than calcium. Therefore the addition of a small amount of
barium or strontium ion to the calcium ion prior to reaction
of ~he latter with phosphate ion will ultimately result in
a barium or strontium-doped hydroxylapatite ceramic which
1~ when used in a dental restorative composition as described
hereinabove would provide sufficient X-ray absorption to
allow detection of the filled tooth. Magnesium which will
also incorporate into the apatite crystal lattice is known
to retard the crystallization of hydroxylapatite while pro-
moting the crystallization of whitlockite ~Eanes et al.,
Calc. Tiss. Res. 2, 32 (1968~]. Thus, the addition of a
small amount ~f magnesium ion ~o the calcium ion prior to
reaction of the latter with phosphate ion will favor the
formation of whitlockite thereby ultimately affording a
whitlockite-enriched biphasic ceramic.
The ceramic materials obtained as described above
were characterized on ~he basis of one or more of the follow-
ing: elemental analysis, d nsity, X-ray diffraction, trans-
mission electron microscopy, polarized light microscopy and
mechanical properties.
The invention is illustrated by the following
; examplés without, however, being limited thereto.
EX~MPLE 1
To a stirred mixture containing 130 ml. of 1.63N
calcium nitrate ~0.212 mole) and 125 ml. of concentrated
-23-
~Loq~582
ammonia there was added dropwise over a period of approxim-
ately 20 minutes a mixture containing 16.75 g. (0.127 mole)
of diammonium hydrogen phosphate, 400 ml of distilled water
and 150 ml. of concentrated ammonia. The resulting suspen-
sion was boiled 10 minutes, cooled in an ice-bath and filter-
ed. The filter cake was pressed with a rubber dam and then
dried overnight a~ 95C. A sample of the resulting, hard,
porous, brittle cake was heated in an electric kiln over a
period of 115 minu~es up to a final temperature of 1230C.
and then cooled to room temperature to give a strong, hard
white translucent ceramic product.
Standard elemental analyses of the final ceramic
product and also of the dried hydroxylapatite prior to
sintering yielded the following results based on Cal0(PO4)6(OH)2:
Dried, Unsintered
Calc'd _~y_~ ~ Ceramic
Ca 39.89% 37.4~ 39.6%
P 18.5% 17.5% 18,9%
E20 0% 1~
Ca~P 1.667 1.65 1~62
Examination of a thin section of the ceramic by
polarized light microscopy at 130X and 352X indicated the
material to be essentially free of whitlockite. The absence
of birefringence and discernible structural features such
as crystallite shape, orientation, boundaries, etc., indicat-
ed a microcrystalline structure. A comparison with the
optical micrographs of a thin section of the sintered com-
pressed tablet reported by Monroe et al. ~supra) showed the
two materials to be structurally dissimilar.
X-ray diffraction measurements were carried out in
-24-
~6S8Z
conventional manner. The interplanar spacings were calculat-
ed and found ~o be virtually identical to the values given
for hydroxylapatite by Donnay et al., Crystal Data, ACA Mono-
gram No. 5,668 (1963~. The X-ray data further indicated the
absence of whitlockite in any amount greater than about 2 to
3 per cent, the minimum concentration sensitivity of the
diffractometer.
EX~MP~E 2
A solution containing 79~2 g, (0.60 mole) of di-
ammonium hydrogen phosphate in 1500 ml. of distilled water
was adjusted to pH 11-12 with approximately 750 ml. of con-
centrated ammonia. Addi~ional distilled water was added to
dissolve precipi~ated ammonium phosphate giving a total
volume ~f 3200 ml. If necessary the pH was again adjusted
to 11-12. This solu~ion was added dropwise over 30-40 minutes
to a vigorously s~ixred solutlon containing 1 mole of calcium
nitrate in 900 ml, of dis~illed water previously adjusted to
p~ 12 with approximately 30 ml. of concentrated aqueous
ammonia and ~hen diluted to a volume ~f 1800 ml, with dis-
tilled water. When the addition was complete, the resultant
gelatinous suspension was stirred an additional 10 minutes,
an~ then ~oiled 10 minute~, removed from the hea~, covered,
and allowed to stand 15-20 hours at room temperature. The
supernatant was decanted and the remaining suspension was
centrifuged at 2000 rpm for 10 minutes, The resul~ing sludge
was re-suspended in 800 ml. of ~istilled water and again
centri~uged at 2000 rpm for 10 minutes. Sufficient distilled
water was added to the reqidual solids to give a total volume
of 900 ml. Vigorous shaking afforded a homogeneous suspen-
sion essentially free of large fragments or aggregates. The
-25-
5~32
entire suspension was poured into a Buchner funnel at one
time and filtered with application of a weak vacuum. When
the filter cake began to crack a rubber dam was applied
and the vacuum increased. After one hour, the dam was re-
moved and the crack-free, intact f ilter cake wa~ transferred
to a flat surface, and dried 15 hours at 90-95C. to give
90-100 g. of white, porous, ~rittle pieces of hydroxylapatite.
Fragmen~s of from one to four cm2 and free of cracks and
flssuxes uere placed in an electric kiln and the temperature
~as rai~ed to 120QC, o~er a period of 100 min, after which
time t~e kiln and its contents were allowed to cool to room
I temperature. There resulted pieces of hard, dense, non-
porous~ w~ite, translucent ceramic material~
Dried, Unsintered
~ ~ : Calc'd Hyd ~
Ca 39.89% 36.5, 36.8% 31.7 ! 38~0%
P 18.5% 21.7% 22.8, 19.0, 18.8
Ca/P 1.667 1.30, 1.31 1.08, 1.55, 1.56
5u~sequent to carrying out the above analyses it
was disco~ered that the ~lytical techni~ue used did not
allow complete dissolution of the samples and the results
are therefore inaccurate and highly variable. Notwithstand-
ing the above analytical data, the su~stantial homogeneity
of this sample was confirmed by the following electron micro-
scopic data. Moreover, the product of Example 3 which was
prepared ~y a procedure essentially identical to the pro-
cedure of Example 2 did have the expected analytical values
and was further characterized as homogeneous hydroxylapatite
by X-ray diffraction and electron microscopy.
Two~tage replica samples were made by shadowing
-26-
i58Z
a collodion replica of the sam~le surface with chromium and
then coating it with carbon. Transmission electron micro-
scopic examination of the replicated samples revealed a
fairly uniform grain size with no evidence of pores or
S second phase precipitate .in either grain boundaries or within
the ~ra~ns t~emselYes in any amount greater than a~out 0.5%,
the ~in~mum concentrat1on sensiti~ity of t~e electron micro-
scope. A sample of the ceramlc was then polished on SiC
paper to 6~ grit~ th n polis~ed to 3 micrometer diamond
1~ paste on a metallographlc wheel covered with fine nylon
.~ cloth~ The sample ~as then etched with 4% hydrofluoric acid
:~ for 30 seccnds~ Replicas were then made of the polished
and etched surface and the~ viewed by electron microscopy.
: Again no second phases were o~served in the grain boundaries,
hDweYer, there was s~a e~idence of small second phase parti-
cles ~n the grain Eulk5
Compression strength and modulus of elasticity
were determined by conven~ional methods and found to be
56,462 psi r 16 ~ 733 psi and 6.3 x 10~ psi, respectively.
Tens~l~ strength was determined ~y the standard
three point ~ending test and found to ~e 9,650 psi + 3,320
pgi .
The thermal expan~ion coefficient was found to be
linear between 25~C. and 225C. wi~h a value of 11 x 10-6/C.
+ 10%.
A ha~dne~ ~alue of 48n was found using the standard
E~oop ~ethod, The ~ame value was o~tained irrespective of
the direction of the applie~ force indicating thereby that
the material was isotropic,
Porosity was determined qualitatively by immersing
-27-
6~82
the test material in a fuchsin dye for 15 minutes, washing
the same with water, drying, and then examining the test
material for traces of remaining dye. This test was per-
formed simultaneously on the non-porous form of the ceramic
provided by this invention, a sintered compressed tablet of
hydroxylapatite~ and a natural toothc The sintered com-
pressed tahlet sho~ed considera~le retention of the dye
w~ereas the no~el ceramic of the present invention and the
natural tooth e~ ited no ~isifile retention of dye, In
another method, the test material was immersed in 6N aqueous
ammonia for 15 minutes, then washed with water, dried and
wrapped in moist litmus paper, Any ammonia remaining entrap- -
ped in surface pores causes the surrounding litmus paper to
turn blue, When this test was performed simultaneously on
the ceramic of this invention, a sintered compressed tablet
O~ hydroxylapatite, and a natural tooth, the litmus paper in
contact with the sintered compressed tablet turned blue
thereby indicating the presence of entrapped ammonia in the
tablet~ No color change was observed in the litmus paper
contacting either the novel ceramic of the present invention
sr the natural tooth.
EXAM
Following a procedure similar to ~hat described
in Example 2 but starting with 3 moles of calcium nitrate
and 1.8 moles of diammonium hydrogen phosphate there was ob-
tained 3~4 g~ of ~hite, firittle~ porous hydroxylapatite~
.. .......... .
Analysis Calc'd Found
Ca 39.89 40.0
P 18,5 18~6
Ca/P 1.667 1~66
-28-
~658;~
Sintering at 1100C. for one hour produced a hard, white,
translucant ceramic having a density of 3.10 g/cm3. X-ray
diffraction indica~ed the material was homogeneous hydroxyl-
apatite. Electron micro copic examination revealed a crys-
S tallite size distribution in the range 0.7 to 3 microns andthe absence of pores or second phase precipitates.
EXAMPLE 4
;~ A. By followin~ a procedure similar to that described
in Example 2 but employing one-half the quantities used
therein, an estima~ed 50 g. of hydroxylapatite was precipita-
ted from aqueous solution. Following centrifugation and de-
cantation the residual mineral sludge was re-suspended in
sufficient water to give a t~tal volume of 1 liter and homo-
genized in a Waring blender for 2 minutes.
B. A mixture containing 0.5 g. of powdered cellulose
(~O.S ~) in 200 ml. of water was blended in a Waring blender
for 3 minutes. A 100 ml. aliquot of the homogeneous aqueous
suspension of hydroxylapatite was then added and the result-
ing mixture blended another 5 minutes. The suspension was
then filtered, and the filter cake dried and sintered
according to Example 2~ The filter cake after drying showed
very little cracking and the ceramic product produced by
sintering was sli~htly porous as indicated by ~he fuchsin
dye test described hereinabove.
C. A mixtuxe containing 0.5 g. of shredded surgical
cotton in 200 ml. of water was blended in a Waring blender
for 45 minute~ or until a nearly homogeneous suspension was
obtained. A 100 ml. aliquot of the homogeneous aqueous sus-
pension of hydroxylapatite described in Example 4A was then
added and blending continued an additional lS minutes. The
_~9_
32
resulting suspension was filtered and the filter cake dried
and sintered according to Example 2. The ceramic product
remained intact and was visibly porous,
EXAMPLE 5
A. A mixture containing 5 g. of collagen (bovine
Achilles tendon~ in 300 ml, of water was blended in a Waring
blender for 5 minu~es, The collagen occluded large amounts
of water to form a thick gelatinous mass~ A small amount of
finely divided collagen ~20-30 mg,) remained in suspension,
B. The suspension of the finely divided collagen
(250 ml.) was decanted and blended in a Waring blender for
5 minutes with a 100 ml, aliquot of the homogeneous aqueous
suspension of hydroxylapatite described in Example 4A,
The resulting mixture was filtered an~ the filter cake dried
and sintered according to Exampl~ 2, The ceramic product re-
mained intact and was substantially non-porous.
; C. Approximately 20 per cent of the thick gelatinous
collagen was blended in a Waxing blender for 6 minutes with
150 ml. of the homogeneous aqueous suspension of hydroxyl-
apa~ite descri~ed in Example 4A, The resulting mixture was
filtered and the filter caXe dried and sintered according
to Example 2. The dried cake prior to sintering remained
intact and had considerable mechanical strength~ The
ceramic produced by sintering was hard, strong and visibly
p~rous.
EXAMPLE 6
Samples of the ceramic product prepared according
to Example 2 were allowed to stand in 1 per cent aqueous
sodium fluoride for 12 hours. These materials together with
sampleq of untrea~ed ceramic and natural teeth were then ex-
-30-
~6S82
posed to lO per cent lactic acid. After 3 days the fluoride-
treated ceramic showed substantially less attack by lactic
acid than either the untreated ceramic or the natural tooth
enamel. When allowed to stand in 1 per cent aqueous sodium
fluoride for 3 days the ceramic was not visibly attacked by
lactic acid after 3 days, and after l month had undergone
only slight decomposition whereas untreated samples were
heavily decomposed,
EX~MPLE 7
By following a procedure similar to that described
in Example 2 bu~ employing one-half the quantities used
therein, an estimated 50 g. of hydroxylapatite was precipita-
ted from aqueous solution. Following centrifugation the
mineral sludge was suspended in sufficient water to give a
total volume of 500 ml. The suspension was divided into
ten equal portions each of which was diluted with 50 ml, of
water and treated with ammonium fluoride as follows: To
samples 1, 2, 3, 4 and 5 there was added respectively 0, O.1,
0.5, l.0 and 2.0 ml. of aqueous ammonium fluoride containing
0.00085 g. F~/ml. Samples 6, 7 and 8 were treated with 0.5,
1.0 and lO.0 ml., respectively, o aqueous ammonium fluoride
containing 0.0085 g. F~/ml. To samples 9 and lO were added
2.0 and 4,0 ml., respectively, of aqueous ammonium fluoride
containing 0.045 g. F~/ml. The suspensions were then shaken
on a rotary shaker for 1.5 hours and filtered. The filter
cakes were pressed 15 minutes with a rubber dam, dried 2 days
at 95C. and then heated in an electric kiln to a temperature
of 1200C. The resulting ceramics wexe ground into fine
powders and sieved through a No, 325 mesh screen. Eighty
milligrams of each of the powder samples was mixed with 80
-31-
ml. o~ pH 4.1 sodiwm lactate buffer solution ~o~4rvl) at 23C.
and shaken on a Burrell wrist-action shaker. At times of
2, 9, 25 and 40 minu~es after mixing, a 3-ml. aliquot was
removed from each sample mixture, immediately filtered to
remove undissolved sample and the amount of solubilized
ceramic determined by a colorimetric assay procedure. The
results are given in Table A. For purposes of comparison
a sintered portion of sample 1 was allowed to stand 4 days
in 1 ml. of 5% sodium fluoride. The solid was separated,
washed thoroughly with water, dried and then subjected to
the above-described dissolution assay as Sample lA. The
results ar~ included in Table A. It will, of course, be
appreciated that the above-described experimental conditions
do not approximate in v1vo conditions but were chosen so as
to permit sufficient solu~ilization of sample within a
reasonable length of time affording thereby an accurate
assessment of the relative effect of fluoride ion concentra-
tion. Thus, in vivo dissolution rates for ceramic hydroxyl-
apatite are expected to be considerably less than the above-
observed rates in the strong lactate buffer.
TABLE A
Relative Dissolution Rates of Fluoridated
Ceramic Hydroxylapatite
Sample Fluoride Conbent (PPM) % Dissolved
No. I~a~r~ --- r.... ~~ ~
1 0 -- 9,2 18.5 32.0 39.7
2 17 19 9.2 18,8 29~3 39.0
3 85 lgOa 8.9 17.6 30.0 38.3
4 170 190 10.3 18,3 30.5 37.5
5 340 216 9,9 18,1 29,7 35.2
~ 850 226 8,~ 17~1 27.7 33~0
71,7~0 470 7~9 18.1 25,7 29,8
817,000 1,4~0 6~7 12,1 19~7 23,3
~18,000 1,700 6.3 11,5 19~7 23,3
3S 10 ~ 9 ~ `13 7 11-7
a. An apparently incorrect assay.
-32-
65~
.. .., . ~ _
Large fragments of dried filter cake about 3-4 mm.
thick prepared accoxding to Example 2 and having Ca/P - 1.64-
1.66 were scored and broken into rectangular plates about
14-15 mm. long and 7-8 mm. wide and a small hole was bored
through one end. One thousand of these plates were then
sintered according ~o Example 2~ and polished to a high gloss
using standard lapidary techniques. The resulting ceramic
bodies having a density of 3.12-3.14 g/cm3 were in the form
of rectangular plates approximately 10-ll mm, long, 4-5 mm,
wide and 2-3 mm. thick and having a hole at one end through
which a length o wire was attached. The plates, which
could thereby be suspended to any desired depth in a test
tube, were used as test surfaces in the evaluation of dental
plaque inhibiting agents as descri~ed hereinabove.
EX~MPLE 9
A solution containing n. 24 mole of diammonium
hydrogen phosphate in 600 ml. of distilled water was adjusted
to pH 11~4 with 340 mlc of concentrated ammonia and the final
volume brought to 1280 ml. with ~istilled water~ This solu-
tion wa~ added ~ropwise over 30 minutes to a vigorously
stirred solution containing 0.4 mole of calcium nitrate in
360 ml. of distilled water previously adjusted to pH 11 with
concentrated ammonia and diluted to a volume of 720 ml, with
distilled water. The resulting suspension was stirred with-
out boiling and 250 ml. aliquots were periodically removed
and the pro~ucts isolated, washed and dried as described in
Example 2. All samples wera then heated one hour at 1100C.
and the composition of the resultant ceramic products deter-
3~ mined by X-ray diffrac~ion. The results are given in Table B~
-33-
~65~3~
TABLE B
Phases observed by
Standing X-ray Diffraction
T~me % %
5SampleStirring Before Elemental Analysis Hydro~yl- Whit-
No. Time Isolation % Ca _ Ca/Papatitelockite
5 min. -- 36.6 18.2 1.5517 83
2 45 min. ~ 21 79
3 2 k~r. -- 36.6 18.0 1.5739 61
10 4 4.5hr -- -- -- 98 2a
7 hr -- 37.0 17.0 1.6898 2a
6 7 hr. 17 hr. 37.2 17~0 1.69100 0
7 24 hr. -- 37,4 17.1 1.69100 0
8 48 hr. -- 37.~ 16.8 1.72100 0
15a. These values border on the minimum concentration
sensitivity of ~he X~ray difractometer (2-3%)
; and the accuracy thereof is thus questionable.
EXAMPLE 10
A, Following a p~ocedure similar to that described in
20Example 2 but using 0.3 moles of calcium nitrate and 0.2
moles of diammonium hydrogen phosphate there was obtained
a hard, brittle, porous product having the following elemental
composition: Ca = 38.3596; P = 19.77%; Ca/P = 1.52. This
material was heate~ 1 hour at 1200~C. to give a strong, hard,
25 non-porous, white, somewhat opas~ue ceramic material compris-
ing approximately 4096 hydroxylapatite and 60% whitlockite as
indicated by X-ray ~iffraction.
B. When the above reaction was carried out wi~h in-
vexse addition of ~he starting materials there was obtained
3n a product comprising approximately 40% hydroxylapatite and
60% whitlockite, and having Ca/P ~ 1.52 and a density of
2.982 g/cm3.
EX~IP~E 11
A solution containing 0.0625 mole o diammonium
35 hydrogen phosphate in 150 ml. of distilled water was treated
with 95 ml. of concentrated ammonia and the final volume
--34--
~9658~
hrought to 320 ml, with distilled water. This solution was
added dropwise over 30 minutes to a vigorously stirred solu-
tion containing ~.1 mole of calcium nitrate and 2.5 ml. of
concentrated ammonia in 180 ml, of distilled water. The re-
sulting suspension was s~irred 5 minutes then cooled in ice
for 45 minutes and the suspended solid isolated, washed and
dried as described in Example 2 to give a hard, brittle,
porous, white solid having the following elemental composi-
tions: Ca = 35.4%; P = 18.59%; Ca/P = 1.46. This material
1~ was heated 1 hour a~ 1350C. ~o give a strong, hard, non-
porous somewhat opaque ceramic product compri~ing approxim-
ately 14~ hydroxylapatite and 86% whitlockite as indicated
by X-ray diffraction.
The products of Examples 1-11 correspond to the
articles of manufac~ure of this invention and have the
physical characteristics thereof as described hereinabove.
The articles of manufacture produced according to
Examples 1, 2, 3, 5B and 6-8 are strong, har~, dense, white,
translucent ceramic bodies comprising substantially pure,
iso~ropic polycrystalline hydroxylapati e free of pores,
and having a compression strength in the approximate range
35,000 to 125,000 psi, a tensile strength in the approximate
range 3,000 to 30,000 psi, a linear thermal coefficient of
expansion in the approximate range 10 to 12 ppm per degree
2S Centigrade, a Xnoop hardness in the approximate range 470
to 500 and a modulus of elasticity of approximately 6 x 106
psi, and ~eing ~haracterized ~y cleavage along smooth curved
planes, and ~y the a~sence of ~irefringence under polari~ed
light.
~he articles of manufacture produced according
-35-
6~8%
to Examples 4 and 5C although comprising the same material
produced according to Examples 1, 2, 3, 5B and 6-8 have in-
troduced therein spaces or pores of varying number and size.
It will be obvious, of course, that the introduction of
pores into said articles effects a change in the physical
properties thereof, for example, a reduction in compressio~
strength, tensile strength, elasticity and hardness.
EXAMPLE 12
A composition suitable as a dental cement and
dental filling agent was prepared as follows:
A To a solution containing 2~ mg, of thé condensa-
tion product of N-phenylglycine and glycldyl methacrylate
(descri~ed in United States Patent 3,200,142 and referred
to therein as NPG-GMA) in 7 ml, of ethanol there was a~ded
2.0 g. of powdered ceramic hydroxylapatite. After swirling
5 minutes the ethanol was evaporated under vacuum at room
temperature and the residual solid was dried 2 hrs. at
1 mm. Hg.
B. An 80-mg. sample of the above material was mixed
with 0.4 mg. of benzyl peroxide and 30 mg. of a 1:2 mixture
of hydroxyathyl methacrylate and the reaction product of
bisphenol A and glycidyl methacrylate as described in United
States Patent 3,066,112 an~ referred to in the art as Bis-GMA.
The resulting mixture was placed in a cylindrical steel mold
wherein it hardened in 3-5 minutes. Compression strength was
determined for four cylindrical plugs so-prepared. The
average value was 24 r 350 psi,
EXAMPLE 13
A mixture comprising 60 parts of powdered ceramic
hydroxylapatite, 13 parts of hydroxyethyl methacrylate, 27
-36~
~0~6582
parts of the condensation product of bisphenol A and glycidyl
methacrylate, 0.3 par~s of N,N-bis-(2-hydroxyethyl)-~-tolu-
idine and 0.8 parts of benzoyl peroxide was blended thoroughly
to give a thin, free-flowing formulation useful as a dental
pit and fissure sealant. The mixture was poured into a
cylindrical steel mold wherein it hardened in about 3 minutes.
Compression str~ngth was determined for seven cylindrical
plugs so-prepared. The average value was 20,400 psi~
~XaMPLE 14
1~ The following is an example of a formulation useful
as a dental filling material.
. To S ml. of 2-propanol was added O.S g. of powdered
ceramic hy~roxylapatite. The 2-propanol was then evaporated
under vacuum at room temperature in order to remove any water
of hydxation from the surface of the ceramic. To 120 mg. of
powdered hydroxylapatite so-treated was added 0.3 mg, of
benzoyl peroxide followed by 40 mg. of a mixture comprising
the condensation product of bisphenol A and glycidyl meth-
acrylate, triethylene glycol dimethacrylate and N,N-bis-(2-
hydroxyethyl)-~-toluidine which mixture is sold by Lee
Pharmaceuticals under the tradename Epoxylite~ HL-72. The
mixture was spatula~ed to a smooth paste and placed into
cylindrical steel molds a~d allowed to stand 4 hours. The
cylindrical plugs were removed from the molds and 3 specimens
were tested and found to have an average compression strength
of 22,300 psi.
EXAMPLE 15
To a solution containing 30 mg. of the condensa-
tion product o N-phenylglycine and glycidyl methacrylate in
7 ml. of ethanol was added with swirling 1 g. of powdered
-37-
z
ceramic hydroxylapatit~. The ethanol was evaporated under
vacuum at room temperature. To a mixture containing 180 mg,
of powdered ceramic hydroxylapatite so-treated and 3,0 mg. of
benzoyl peroxide was added to 74 mg. of a mixture containing
60 parts of the condensation product of bisphenol A and
glycidyl methacrylate and 40 parts of triethylene glycol
dimethacrylate and the resulting aggregate spatulated to a
smooth pas~e which was placed into cylindrical steel molds
and allowed to stand 3 hours. The cylindrical plugs were
removed from the molds and 4 specimens were tested and
found to have an average compression strength of 22,300 psi~
EXAMPLE 16
A composi~ion suitable as a dental and orthodontic
cement or as a temporary dental filling agent was prepared
by mixing together 1~0 mg. of powdered ceramic hydroxylapa-
tite, 300 mg, of zinc oxide and 300 mg, of 40% aqueous poly-
acrylic acid. The resulting mixture was placed in cylindri-
cal steel molds wherein it hardened in about 3-5 minutes.
The cylindrical plugs were removed from the molds and 4
specimens were tes~ed and found t~ have an average compres-
sion strength of 12,400 psi. Another 5 specimens were found
to have an average diametral tensile strength of 1630 psi,
The 40% aqueous polyacrylic acid and the zinc oxide were ob-
tained as the liquid and solid components respectively of a
commercial polycarboxylate cement available from ESPE G,m.b.H.,
West Germany, under the tradename Durelon~,
EX~MPLE 17
A composition suita~le as a dental aement and
dental filling agent was prepared by mixing together 6 parts
by weight of 40 per cent aqueous polyacrylic acid with a mix-
-38-
513~:
ture containing 6 parts by weight of powdered ceramic hydroxyl-
apatite and 4 parts by weight of zinc oxide. The resulting
composition had a setting time of about 5 to 10 minutes. The
40 per cent aqueous polyacrylic acid and the zinc oxide were
obtained as the liquid and solid components respectively of
a commercial polycarboxylate cement available from ESPE
G.m.b~H,, West Germany, under the tradename Durelon~.
EXAMPLE 18
The following is an example of a dental filling
composition:
_ Per cent by Wei~ht
Styrene modifi~d polyester resin
~Glidden Glidpol G-136) 29.2
Benzoyl peroxide 0.7
Styrene 0.6
MethacryloY.ypropyltrimethoxysilane 1.5
Ceramic hydroxylapatite 6~.O
EX~MPLE 19
The following is an example of a composi~ion sui~-
able as a dental cement, cavity liner and pulp capping agent:
In redient
Epo~y resin (Union Carbide ERL2774) 67
N-3-oxo~ dimethylbutylacrylamide 23
Ceramic hydroxylapatite 10
EXAUPLE 20
The following is an example of a composition suit-
a~le for the fa~rication of an artificial tooth or set of
teeth.
A mixture containing 60 parts by weight of ceramic
hydroxylapatite of approximately 150 to 200 mesh and 40 parts
-39-
~L~396~Z
by weight of powdered polymethyl methacrylate is blended
with approximately 15 parts by weight of liquid monomeric
methyl methacrylate and the resulting mixture allowed to
stand in a sealed vessel at room temperature until the mate-
rial no longer adheres to the walls of the vessel and has a
non-sticky plastic consistency. The material is then packed
into an appropriate mold and the mold and its contents
immersed in water which is heated to ~oiling over a period
of about one hcur and maintained at that temperature for 39
1~ minutes. The mold is then allowed to air cool for about 15
minutes and finally cooled in cold tap water.
The bio-compatibility of the novel ceramic form of
hydroxylapatite afforded by the present invention was con-
firmed by implantation studies wherein it was found that no
inflammatory response was elicited when chips of the ceramic
prepared according to the method of Example 1 were implanted
intraperitoneally in rats or when inserted subcutaneously on
the backs of rabbits, and no resorption of the ceramic was
evident after 28 days,
Pellet~ of ceramic hydroxylapatite prepared by a
method similar to that described in Example 3 were surgically
implanted in ~he femurs of dogs. The implants were monitored
in vivo by periodic X-ray. After respective periods of one
month and six months the animals were sacrificed and the
femurs containing the implants were removed~ The femurs were
sectioned at the implant site and examined ~y both optical and
scanning electron microscopy. Both the one-month and six-
months implants were characterized ~y normal healing, strong
~inding of new bone to the implant surface with no interven-
ing fibrous tissue, no evidence of inflammation or foreign
~ody response and no resorption of the implant material.
-40-
