Chemical processing of CaHPO4·2H2O: Its conversion to hydroxyapatite

Article abstract of DOI:10.1111/j.1151-2916.2004.tb07490.x

The aim of this paper is to develop a robust chemical process to synthesize Na- and K-doped brushite (DCPD: dicalcium phosphate dihydrate, CaHPO ₄·2H₂O), a potential starting material for bone substitutes. The powders were synthesized by using sodium phosphate and potassium phosphate and aqueous solutions containing calcium chloride at room temperature, followed by drying at 37°C. DCPD powders thus formed were found to contain 460 ppm K and 945 ppm Na. On calcination in air, these powders readily transformed into monetite (DCPA: dicalcium phosphate anhydrous, CaHPO₄) first, and then into Ca₂P₂O₇ (calcium pyrophosphate). Na- and K-doped DCPD powders were shown to completely transform, in less than 1 week, into poorly crystalline carbonated apatite on immersion in an acellular simulated/synthetic body fluid (SBF) solution at 37°C. The Tris (i.e., tris(hydroxymethyl)aminomethane) buffered SBF solution used in this study had a carbonate ion concentration of 27 mM equal to that of human plasma. DCPD powders of this study displayed a notable apatite-inducing ability. This finding suggests the use of these DCPD powders as the starting materials for potential bone substitutes, which can be easily manufactured in aqueous solutions friendly to living tissues, at temperatures between room temperature and 37°C.

Full text of DOI:10.1111/j.1151-2916.2004.tb07490.x

J. Am. Ceram. Soc., 87 [12] 2195–2200 (2004)
journal
Chemical Processing of CaHPO ⅐2H O:
4
2
Its Conversion to Hydroxyapatite
A. Cuneyt Tas* and Sarit B. Bhaduri**
School of Materials Science and Engineering, Clemson University, Clemson, South Carolina 29634
The aim of this paper is to develop a robust chemical process
to synthesize Na- and K-doped brushite (DCPD: dicalcium
DCPD transforms (by losing its crystal water) into DCPA on
5 6,7 8
heating at or above 110°C. Both DCPD and DCPA phases are
successfully used as starting materials in the preparation of the
phosphate dihydrate, CaHPO ⅐2H O), a potential starting
4
2
material for bone substitutes. The powders were synthesized
by using sodium phosphate and potassium phosphate and
aqueous solutions containing calcium chloride at room tem-
perature, followed by drying at 37°C. DCPD powders thus
formed were found to contain 460 ppm K and 945 ppm Na. On
calcination in air, these powders readily transformed into
monetite (DCPA: dicalcium phosphate anhydrous, CaHPO4)
first, and then into Ca P O (calcium pyrophosphate). Na- and
powder components of self-hardening apatitic calcium phosphate
9,10
cements. However, recent reports
are directed toward the
development of self-hardening orthopedic cements whose final
product is DCPD. Such formulations have superior in vivo resorb-
ability, as opposed to conventional apatitic cements. The scientific
basis behind this development can be clearly explained by the
11
dissolution data published by Tang et al. Relying on the
2
2
7
experimental solubility values of some of the calcium phosphate
K-doped DCPD powders were shown to completely transform,
in less than 1 week, into poorly crystalline carbonated apatite
on immersion in an acellular simulated/synthetic body fluid
1
1
phases recently reported by Tang et al., it is seen that DCPD has
Ϫ4
Ϫ2
Ϫ1
a dissolution rate of 4.26 ϫ 10 mol⅐m ⅐min at a pH value of
.5, and this rate is only about 3.4 times greater than that of
5
(
SBF) solution at 37°C. The Tris (i.e., tris(hydroxymethyl)ami-
Ϫ4
Ca (PO ) (i.e., 1.26 ϫ 10 ). To compare these, the dissolution
rate for carbonated apatite was reported by the same researchers
to be 1.42 ϫ 10
nomethane) buffered SBF solution used in this study had a
carbonate ion concentration of 27 mM equal to that of human
plasma. DCPD powders of this study displayed a notable
apatite-inducing ability. This finding suggests the use of these
DCPD powders as the starting materials for potential bone
substitutes, which can be easily manufactured in aqueous
solutions friendly to living tissues, at temperatures between
room temperature and 37°C.
3
4 2
1
1
Ϫ6
.
DCPD powders can easily be synthesized in aqueous solutions
at room temperature by using soluble calcium (e.g.,
Ca(NO
) ⅐4H O, CaCl ⅐2H O, or Ca(CH COO) ⅐H O) and phos-
3 2 2 2 2 3 2 2
phate (e.g., NH H PO , (NH ) HPO , Na HPO , NaH PO ,
4
2
4
4 2
4
2
4
2
4
KH PO , or K HPO ) salts on adjusting the Ca/P molar ratio to
2
2–15
4
2
4
1
1
.
The use of Na- and/or K-containing starting chemicals
during the synthesis of DCPD powders may also result in the
I. Introduction
16–19
production of Na- and/or K-doped DCPD.
On the other hand,
1
pure DCPD powders can also be synthesized, for instance, by
OTENTIAL bone substitute materials must be actively resorbed
reacting a suspension of Ca(OH) with stoichiometric amounts of
2
P
in vivo by the osteoclasts (cells that are able to resorb the fully
2
0,21
H PO , as long as the solution pH is kept in the acidic range.
3
4
mineralized bone), as they are equipped with a variety of enzymes,
which lower the local pH to a range of 3.9 to 4.2. This occurs via
a process called cell-mediated acidification in which the host bone
can deposit new bone on those resorption sites by the osteoblasts
1
7,18
Kumar et al.
reported previously that electrodeposited
DCPD, which was doped with monovalent cations, such as
potassium, might result in more rapid transformation into apatitic
calcium phosphates on soaking the samples in Hanks balanced salt
(
cells that build the extracellular matrix and regulate its mineral-
2
2
solution (HBSS) of pH 6.8. HBSS is the historical origin of
simulated body fluid (SBF) solutions of pH 7.4, which were
ization). Bulk ceramics in the form of porous prismatic blocks,
self-hardening cements, granules, coatings obtained by the high-
temperature thermal spray techniques, injectable pastes, etc., are
used as implant materials. For their successful application, they
should be able to fully take part in the bone remodeling processes
and must be eventually resorbed and fully replaced by the new
bone within a year following the implantation. Either synthetic or
bovine calcium hydroxyapatite (Ca (PO ) (OH) ) bioceramics
heated at or above 1100°C during their processing do not resorb
well and do not take part in the in vivo bone remodeling processes
2
3
popularized by Kokubo over the last decade. The main differ-
ence between an HBSS solution and SBF lies in the value of the
Ca/P molar ratios. HBSS has a Ca/P ratio of 1.823, whereas the
same in SBF is 2.50. Owing to its lower Ca/P molar ratio, an HBSS
solution, in contrast to SBF, needs quite long times to induce
2
2
4
1
0
4 6
2
apatitic calcium phosphate formation. However, to raise the Ca/P
ratio of HBSS to 2.50, one only needs to add 70.5 mg of
CaCl ⅐2H O to 1 L of a commercially available HBSS solution.
2
2
3
,4
within the aforementioned time frame. In general, resorbability
of highly crystalline, sintered bovine-origin apatitic calcium phos-
Therefore, soaking DCPD powders in SBF, instead of HBSS
solutions, to test their apatite inducing ability would be more
viable. Tas-SBF used in this study was a Tris-HCl buffered
2
Ϫ
phates is poor, due to the volatilization of initially present HPO
and CO3 ions.
4
2
Ϫ
Ϫ
solution with a HCO3 ion concentration equal to 27 mM, whose
2
5
preparation details were previously explained elsewhere.
The main purpose of this study is to develop a robust chemical
synthesis procedure for the manufacture of Na- and K-doped
DCPD powders, and then study their transformation into apatitic
D. W. Johnson Jr.—contributing editor
2
6
calcium phosphates by immersing them in an acellular and
metastable (with respect to hydroxyapatite nucleation) SBF solu-
2
5
tion over the duration of 36 h to 5 weeks. High-temperature
calcination behavior of the alkali-doped DCPD powders is also
reported.
Manuscript No. 10897. Received March 4, 2004; approved August 5, 2004.
*
*
Member, American Ceramic Society.
*Fellow, American Ceramic Society.
2
195

2
196
Journal of the American Ceramic Society—Tas and Bhaduri
Vol. 87, No. 12
II. Experimental Procedure
The synthesis procedure used to form Na- and K-doped DCPD
calcium pyrophosphate initially functioned as an osteoconductive
scaffold, which consecutively and seamlessly took part (within 3
months) in the bone remodeling process. All of the powders (i.e.,
DCPD, DCPA, Ca P O , and the apatitic calcium phosphates
formed) of this study will need to undergo such in vivo tests to
evaluate their biocompatibility and resorbability.
powders simply consisted of preparing two solutions. Solution A is
prepared as follows: 4.127 g of KH PO was dissolved in 3.5 L of
2
2 7
2
4
deionized water, followed by the addition of 15.065 g of
Na HPO , which resulted in a clear solution of pH 7.4 at room
2
4
Calcination behavior of the platelike DCPD powders (Figs. 1(B)
and (E)) of the current work presented a typical case for the
temperature (22 Ϯ 2°C). Solution B (pH 7.3) was prepared by
dissolving 20.068 g of CaCl ⅐2H O in 250 mL of deionized water.
3
2
2
2
thermally induced transformation of an orthophosphate into a
pyrophosphate according to the following reactions:
Solution B was then rapidly added to solution A and the precipi-
tates formed were aged for 80 min at room temperature, by
continuous but moderate stirring (final solution pH 5.3). Solids
recovered from their mother liquors were dried for 2 days at 37°C
in an air atmosphere to obtain 16.85 g of Na- and K-doped DCPD
powders.
The calcination behavior of these powders was determined by
isothermal heatings over the temperature range of 300° to 1000°C,
with 6 h of soak time at the peak temperatures. Simultaneous
TG/DTA runs (room temperature to 1000°C, 5°C/min) were also
performed, in a static air atmosphere, on the DCPD samples.
Powder samples were characterized, at all stages, by XRD (XDS
2CaHPO
⅐2H
O(s) 3 2CaHPO
(s) ϩ 4H
O(g)
(1)
(2)
4
2
4
2
2
CaHPO (s) 3 Ca P O (s) ϩ H O(g)
4
2
2
7
2
These reactions were experimentally confirmed to take place by
the TG/DTA analysis (Fig. 1(C)). ␤-Ca P O phase obtained after
2
2 7
8
50° and 1000°C calcinations conformed to the ICDD PDF 9-346.
On the other hand, ␣-Ca P O phase (ICDD PDF 9-345) was
2
2 7
observed in the samples calcined at 500° and 700°C (Fig. 1(D)).
DCPD is known to be a nucleation precursor, in aqueous
1
2
solutions, to the apatitic calcium phosphates. DCPD transforms
into the thermodynamically more stable, apatitic calcium phos-
2
000, Scintag, Sunnyvale, CA), SEM (S-3500, Hitachi Corp.,
Tokyo, Japan), FTIR (Nicolet 550, Thermo-Nicolet, Woburn,
MA), ICP-AES (Model 61E, Thermo Jarrell Ash, Woburn, MA),
and TG/DTA (Model 851e, Mettler-Toledo, Inc., Columbus, OH)
analyses.
3
3
phate, by a dissolution–reprecipitation mechanism. DCPD has a
relatively low solubility in water, and thus water alone could not be
3
4
sufficient to drive the reprecipitation mechanism. However, if
2
ϩ
the aqueous medium of DCPD immersion contains Ca ions, then
the process will readily proceed according to the following
Hydrolytic conversion of Na- and K-doped DCPD powders into
poorly crystalline, apatitic calcium phosphate was studied by
soaking those in a Tas-SBF solution at 37°C; 250 mg portions of
3
5
reaction:
2
5
DCPD powders were placed in 25 mL of the SBF solution (2.5
6
CaHPO ⅐2H O ϩ ͑4 Ϫ x͒CaCl ϩ ͑2 Ϫ x͒H O 3
2
ϩ
2Ϫ
Ϫ
ϩ
4
2
2
2
mM Ca , 1 mM HPO , 27 mM HCO , 142 mM Na , 5 mM
4
3
ϩ
2ϩ
2Ϫ
Ϫ
K , 1.5 mM Mg , 0.5 mM SO4 , 125 mM Cl , Tris-HCl
Ca10Ϫx(HPO ) (PO )6Ϫx(OH)2Ϫx ϩ ͑8 Ϫ 2x͒HCl ϩ 12H O
4 x 4 2
buffered, pH 7.4), in plastic vials. During the conversion process,
(
3)
1
5 mL aliquots of solutions were replenished with a fresh SBF
solution at every 36 h. The experiment continued in 8 identical
vials for solid sample recovery times of 36 h, 72 h, 1 week, 1.5
weeks, 2 weeks, 3 weeks, 4 weeks and 5 weeks. The vial contents
were then filtered and washed with 400 mL of deionized water and
dried at 37°C for 48 h, before characterization runs.
Apatite formed in reaction (3) is termed Ca-deficient hydroxyap-
3
6
atite (CDHA, molar Ca/P ϭ 1.50), and this formula represents
the family of apatites formed at neutral pH. However, this formula
is still a simplified version since it does not account for the alkali
3
7
and carbonate ions incorporated into the structure. Driessens et
3
8
al.
have studied the synthesis of resorbable, Na- and
K-containing CDHA self-setting cements. Under highly alkaline
conditions (i.e., pH Ͼ10) of synthesis and precipitate aging, the
formed apatitic calcium phosphates would have lesser amounts of
III. Results and Discussion
3
9
Chemically synthesized powders were characterized by using
XRD, FTIR, SEM, ICP-AES, and TG/DTA to be single-phase, Na-
and K-doped (460 and 945 ppm, respectively) CaHPO ⅐2H O, as
shown in Figs. 1(A) (the inset is the FTIR data) through 1(C).
DCPD powders were observed to have an elongated platelike
morphology, with plate sizes varying over the range of 20 to 125
m. DCPD is known to crystallize in the monoclinic space group
Cc with the lattice parameters a ϭ 6.359, b ϭ 15.177, c ϭ 5.81 Å,
ϭ 118.54°. As a function of increasing calcination tempera-
vacancies in their OH sites. If, for instance, NH OH were used
4
to raise the pH value above 10 during chemical synthesis, the
hydroxyapatite precipitates formed may also have some NH ions
4
2
4
3
7
incorporated into their structure. Fully hydroxylated apatite
samples are known to have an extremely basic surface, and on their
immersion, they even cause the pH of the respective aqueous
4
0
␮
medium to rise to above 10. Such high pH values on the surfaces
of implant materials are not well tolerated by the live tissues, and
may lead to cell necrosis.
2
7
␤
ture, as shown in Figs. 1(D) to (E) (XRD and FTIR data,
Doping of DCPD powders with small amounts of Na and K
(460 and 945 ppm, respectively) during their synthesis, as exem-
plified in this study, imparted a neutral surface pH (i.e., 6.90–7.10)
to those, in comparison to pure, commercially available slightly
acidic DCPD powders. Because of this acidity, bone substitutes
made by using commercial DCPD powders until now were known
to cause a certain degree of tissue inflammation during the first
respectively), DCPD first transformed into triclinic CaHPO and
4
then to Ca P O . CaHPO has the following lattice parameters:
2
2
7
4
a ϭ 6.910, b ϭ 6.627, c ϭ 6.998 Å, ␣ ϭ 96.34°, ␤ ϭ 103.82°, and
␥
ϭ 88.33°. Its structure consists of CaHPO4 chains bonded
27
together by Ca–O bonds and three types of hydrogen bonds.
The platelike morphology of transparent DCPD crystals (Fig.
(B)) was preserved even after conversion into microporous
1
0,41
1
weeks of in vivo implantation.
The Na- and K-doped powders
Ca P O by heating in air at 1000°C for 6 h (Fig. 1(E)). TG/DTA
of this study, which have neutral surface pH values, are expected
to circumvent this problem.
2
2 7
data of our DCPD powders (i.e., Fig. 1(C)) agreed perfectly with
2
8
those reported by Joshi et al. We observed that DCPD trans-
formed to DCPA at around 180°C with a weight loss of 20.3%, and
the DCPA to Ca P O transition started above 440°C, with a
Therefore, to examine the dissolution–reprecipitation mecha-
nism of our DCPD powders as a function of time, we selected a
Ϫ
25
Tris-buffered, carbonated (27 mM HCO3 ) SBF solution of pH
2
2 7
further 6% weight loss. FTIR data presented in Figs. 1(A)
7.4 as the immersion medium. If we were to soak the DCPD
1
1,42
(
as-formed DCPD) and 1(F) (as a function of calcination temper-
powders in pure water,
we would have mostly seen its
2
8–30
ature) also coincided very well with those in the literature.
sluggish dissolution over a period of 1 month. Ca and Cl ions
present in the SBF solutions provided the driving force for reaction
(3). As seen in the XRD data of Fig. 2(A) for the DCPD powders
immersed in SBF solutions at 37°C, even after 72 h of soaking a
significant amount of CDHA was formed as predicted by reaction
3
1
Lee et al. recently tested commercial powders of Ca P O as
2
2 7
a synthetic bone graft material in comparison to hydroxyapatite.
They reported a superior resorbability for Ca P O in their
2
2 7
canine-based proximal tibia model. The authors concluded that the

December 2004
Chemical Processing of CaHPO ⅐2H O
2197
4
2
Fig. 1. (A) XRD and FTIR data of as-synthesized DCPD powders. (B) SEM photomicrograph of as-synthesized DCPD powders. (C) TG/DTA data for the
as-synthesized DCPD powders. (D) XRD data of DCPD powders as a function of calcination temperature. (E) SEM photomicrograph of DCPD powders
calcined at 1000°C for 6 h; resultant phase is now Ca P O . (F) FTIR data of DCPD powders as a function of calcination temperature.
2
2 7
(
3). By the end of 1 week of soaking time, all of the crystal peaks
human blood plasma. FTIR data given in Fig. 2(B) for those
samples clearly indicated the same trend. The recognition of the
characteristic bands in the FTIR spectra of apatite and DCPD
phases have been unequivocally established in various referenc-
of DCPD disappeared from the XRD patterns. This meant that the
DCPD-based calcium phosphates would readily transform into
bone mineral-like, apatitic calcium phosphates within less than 1
week, when soaked at 37°C and pH 7.4 in a solution simulating the
2
5–30
es.
FTIR spectra of Fig. 2(B) confirmed that the carbonated

2
198
Journal of the American Ceramic Society—Tas and Bhaduri
Vol. 87, No. 12
Fig. 2. (A) XRD data of DCPD powders soaked in SBF for various times (* indicates DCPD peaks). (B) FTIR data of DCPD powders soaked in SBF for
various times. (C) Powders soaked in SBF at 37°C for 36 h; a phase mixture of DCPD and CDHA. (D) Powders soaked in SBF at 37°C for 1 week;
single-phase CDHA.
nature of the apatitic calcium phosphate initially formed was
gradually developing with an increase in soaking time. Human
bones contain a significant amount of carbonate ions, i.e., 5–7
wt%. SEM photomicrographs given in Figs. 2(C) and (D), as a
function of immersion time in SBF, depicted the evolution of the
characteristic morphology of needlelike CDHA.
morphology. They were shown by XRD to be highly crystalline,
single-phase DCPD. These crystals were regarded as the early-
stage crystallization products of the synthesis process reported in
this study.
Subsequently, to picture the dissolution behavior of those
DCPD crystals, a 100 mg portion was placed into 10 mL of a
2
5
From X-ray or neutron crystallographic studies, the crystal
structure of DCPD is known to contain compact sheets or bilayers
freshly prepared Tas-SBF solution. Following 3 h of immersion
at 37°C in SBF, the DCPD crystals were washed with water and
dried at 37°C, overnight. The XRD pattern of the samples again
indicated single-phase DCPD, as shown in Fig. 1(A). The SEM
photomicrograph given in Fig. 3(B) shows the dissolution of
2
7
parallel to the (010) plane. One bilayer was found to present
sheets of calcium and phosphate ions, while the other bilayer
4
3
comprised water molecules. Flade et al. reported that the
4
3
hydrated bilayer was the terminating layer at the surface of the
DCPD, revealing the aforementioned bilayer structure, which
until now could only be ascertained by using crystallographic
techniques. The reprecipitation leg of this mechanism, which leads
to the apatitic calcium phosphate formation, subsequently takes
place at the later stages of SBF immersion, as shown above. SBF
solutions of pH 7.2 to 7.4 are supersaturated with respect to apatite
(i.e., Ca/P molar ratio ϭ 2.50). Therefore, the only phase that can
precipitate from such neutral pH solutions is carbonated apatitic
phosphate.
(
010) face in aqueous solutions, and dissolution of DCPD must
start from the ledges.
To examine the dissolution behavior of DCPD more clearly, we
modified our synthesis process slightly. In that experiment, we
placed a 30 mL aliquot of freshly prepared solution A (its
preparation is described in the Experimental Procedure section)
®
into a 50-mL-capacity glass beaker covered with Parafilm . The
beaker was then heated to 37°C in a constant-temperature oven.
One minute after the injection (with a syringe and needle) of a 1
mL portion of solution B into that beaker, solution pH was
recorded as 5.5 at 37°C, and it was rapidly cooled to 0°C by
immersing it into an ice-water bath. The precipitates were sepa-
rated immediately from the mother liquor by centrifugal filtration,
and washed with water. The formed precipitates as shown in the
optical micrograph given in Fig. 3(A) had a star- or rosette-like
The bilayers inherent in DCPD crystals are known to consist of
calcium and phosphate sheets separated by another sheet of water
4
3
molecules. This sheet and ledge morphology has been revealed
in the SEM micrograph of Fig. 3(B) after soaking DCPD crystals
in an SBF solution at 37°C for 3 h. The presence of Na and K
4
4
dopant ions (which help to increase the crystallographic disorder,
and thus, the overall solubility of the crystals) within the calcium

December 2004
Chemical Processing of CaHPO ⅐2H O
2199
4
2
Fig. 3. (A) Early-stage crystals of DCPD formed in 1 min. (B) Dissolution of DCPD crystals in SBF at 37°C, revealing the ledge structure.
ledges is believed to enhance the hydrolysis kinetics of DCPD. The
hydrolysis product is carbonated, calcium-deficient hydroxyapatite
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6
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4 2
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Ϫ
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7
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4
2
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9
2
0
10
ported for their enhanced resorbability. Moreover, the platelike
or needlelike morphology observed in chemically prepared
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IV. Conclusions
1) The chemical process outlined here allowed the robust
synthesis of biocompatible Na- and K-doped DCPD powders, with
a unique platelike morphology, by starting with aqueous solutions
at the physiologic pH (7.4) and temperature (37°C) conditions.
1
3
G. R. Sivakumar, E. K. Girija, S. Narayana Kalkura, and C. Subramanian,
“
Crystallization and Characterization of Calcium Phosphates: Brushite and Monetite,”
(
Cryst. Res. Tech., 33, 197–205 (1998).
14
J. S. Sorensen and H. E. Lundager Madsen, “The Influence of Magnetism on
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(
2) The results showed that it was possible to preserve this
particle morphology even though the powders were later converted
to Ca P O by high-temperature calcination.
3
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2
2 7
1
7
(
3) Finally, this study also exemplified a simple procedure for
producing carbonated apatitic calcium phosphate powders, after
straightforward immersion of DCPD powders in SBF solutions
pH 7.4) at 37°C. The highest temperature of processing hereby
used in the manufacture of bulk, poorly crystalline apatite powders
was 37°C.
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