Chemical Engineering Journal 221 (2013) 55–61

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Chemical Engineering Journal

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Preparation of highly purified b-tricalcium phosphate ceramics with amicrodispersion process

1385-8947/$ - see front matter � 2013 Elsevier B.V. All rights reserved.http://dx.doi.org/10.1016/j.cej.2013.01.044

⇑ Corresponding author. Tel.: +86 10 62783870; fax: +86 10 62780304.E-mail address: gsluo@tsinghua.edu.cn (G.S. Luo).

L. Du, Y.J. Wang, Y.C. Lu, G.S. Luo ⇑The State Key Laboratory of Chemical Engineering, Department of Chemical Engineering, Tsinghua University, Beijing 100084, People’s Republic of China

h i g h l i g h t s

" A novel continuous process forpreparing b-Ca3(PO4)2 nanoparticleswas developed.

" Highly pure b-Ca3(PO4)2

nanoparticles were finely prepared." The mixing efficiency governs the

mass transfer and reactions." The relation of synthesis reaction

and microdispersion wasinvestigated.

" The possible mechanism has beenprovided to explain the side reaction.

g r a p h i c a l a b s t r a c t

a r t i c l e i n f o

Article history:Received 26 September 2012Received in revised form 2 January 2013Accepted 8 January 2013Available online 4 February 2013

Keywords:MicroreactorMixing performanceb-Tricalcium phosphateNanoparticles

a b s t r a c t

In this study, a novel continuous process for preparing b-tricalcium phosphate (b-Ca3(PO4)2, b-TCP) nano-particles was developed with low-price calcium hydroxide and phosphoric acid as the reactants. A micro-orifice dispersion microreactor was designed to realize the fast microreaction process. The relation of thesynthesis reaction and microdispersion was investigated. The side reaction was eliminated with the fastand uniform mixing process. Highly pure b-TCP nanoparticles were finely prepared. The experimentalresults showed that the b-TCP nanoparticle crystal shape and size as well as the Ca/P molar ratio couldbe well controlled using the microdispersion process. The size of b-TCP nanoparticles ranged from 80to 120 nm.

� 2013 Elsevier B.V. All rights reserved.

1. Introduction

Materials of calcium phosphate ceramics have received a greatdeal of attention for their biocompatibility and similarity of thenatural bone crystallographic structure. Because of these proper-ties, these materials are used primarily in medical and biologicalapplications [1–5]. Especially b-tricalcium phosphate (b-Ca3(PO4)2,b-TCP) has been widely used as material for bone replacement[6–8]. Because of the outstanding biological responses tophysiological environment, b-TCP constitutes the major inorganic

phase of human hard tissue, such as bone and teeth [9,10]. b-TCPnanoparticles with needle shape and length ranging from 100 to150 nm, which have been proven to be particularly active in vivo[11]. Furthermore, it is well known that the phase purity of b-TCP is important for successful bone generation [12,13]. The puri-fied b-TCP with a Ca/P molar ratio equal to 1.5 was reported as safe,non-toxic, biocompatible material and the subsequent applicationsalso got good long-term results [11,14]. Thus the controllablepreparation of b-TCP nanoparticles with uniform particle size,morphology and Ca/P molar ratio could provide great potential inapplications [15].

The synthesis reactions of b-TCP can be described as follows:

Notations

d length of b-TCP nanoparticles (nm)FC flow rate of continuous phase (mL/min)FD flow rate of disperse phase (mL/min)Num number fraction of nanoparticle size

x mole fraction of ionsXS segregation index

Fig. 1. The experimental set-up for measuring the mixing performance andpreparing b-TCP nanoparticles: r circulation for synthesis of b-TCP s UV analysisfor mixing performance.

56 L. Du et al. / Chemical Engineering Journal 221 (2013) 55–61

9Ca2þ þ 5PO3�4 þHPO2�

4 þ OH� ! Ca9ðHPO4ÞðPO4Þ5ðOHÞ ð1Þ

Ca9ðHPO4ÞðPO4Þ5ðOHÞ ���!900�C 3Ca3ðPO4Þ2 þH2O ð2Þ

The generation of HPO2�4 accelerates the incorporation into the

Ca9(HPO4)(PO4)5(OH) (CDHA) structure. But the reaction of HPO2�4

with Ca2+ takes place at the same time, which brought a seriouscontradiction. A slight variation in the synthesis can generate vari-ations in the composition of the final product as pyrophosphate(Ca2P2O7, as shown in Eq. (3)), which results in Ca/P ratio <1.5 aftercalcination.

2CaHPO4 ���!550�C Ca2P2O7 þH2O ð3Þ

Many methods have been developed to produce b-TCP nanopar-ticles, including solid-phase reaction synthesis [16], the sol–gelmethod [17], microemulsion synthesis [15], and the precipitationmethod [18–20]. Various reactants with relatively high price suchas Ca(NO3)2, CaCl2, (CH3COO)2Ca, (NH4)H2PO4, and Na3PO4 wereemployed to control the ion release rate and Ca/P ratio. Even HCl,Na2SO4, CaCO3, methanol, etc. were utilized sometimes, whichmade subsequent separation difficult.

Some researchers have attempted to produce highly pure withlow-price raw materials, such as Ca(OH)2 suspensions and H3PO4

aqueous solution. To precisely control the incorporation of HPO2�4

into the CDHA structure, most of the reaction and ripening timewas extended. Some strategies required high temperature (60–100 �C) or long reaction time (8–48 h) [3,10]. In the traditional stir-red batch reactors, it is extremely difficult to control the rate anduniformity of the reactants mixing together as well as theresidence time, which causes the mass transfer efficiency greatlyreduced. Thus CaHPO4 particles with relatively large particle sizeare generated and a lot of time for the converse reaction in Eq.(3) is required, resulting in an unstable Ca/P molar ratio.

In the last two decades, microreactors have been successfullyused to enhance heat and mass transfer efficiency and generateuniform reaction environments. In these micro-structured reac-tors, one phase can be mixed with another phase at micron scale.The mixing process can be controlled by the flow rate, as well asthe geometry and physical properties of the device [21]. Thus mic-roreactors have been used as a powerful tool for the fast prepara-tion of nanoparticles in chemical reaction systems. A variety ofnanoparticles have been prepared using different microdevices[22–24]. In our previous study, a membrane dispersion microreac-tor has been developed and successfully used to synthesizenanoparticles in homogeneous and heterogeneous mixing systems[25–28].

In this study, we present a new preparation technology forb-TCP nanoparticles. Low-price calcium hydroxide (Ca(OH)2)suspension as the Ca-source and phosphoric acid (H3PO4) solutionas the P-source were employed. A micro-orifice dispersion mic-roreactor was developed to control the fast and uniform mixingprocess. The mixing performance was characterized by utilizingparallel competing reactions. b-TCP nanoparticles with uniformsize and Ca/P molar ratio were successfully prepared using thenew technology and the influence of the operating conditionswas studied.

2. Materials and methods

2.1. Mixing performance

To characterize the mixing performance of the microreactor, the‘‘Villermaux/Dushman method’’ was utilized, which employs theparallel competing reactions. The reaction formulas are shown asfollows:

H2BO�3 þHþ ! H3BO3 ðquasi� instantaneousÞ ð4Þ5I� þ IO�3 þ 6Hþ ! 3I2 þ 3H2O ðfastÞ ð5ÞI2 þ I� $ I�3 ð6Þ

Based on the absorbance of the product triiodide measured byspectrophotometry (UV–vis recording spectrophotometer,UV-8345, Hewlett–Packard) at 353 and 286 nm, a segregationindex, XS, is defined to quantify the micromixing performance[29,30], which is defined as:

XS ¼Y

YST¼

CI2 þ CI�3

� �V

nHþ ;0

6CIO�3 ;0 þ CH2BO�3 ;0

3CIO�3 ;0

!ð7Þ

In Eq. (7), n and C are the mole amount and mole concentrationof the subscript species while the subscript 0 represents the initialstate; Y is the ratio of acid molar amount consumed in reaction (5)divided by the entire acid molar amount; YST is the value of Y whenthe mixing process is infinitely slow. The value of XS lies between 0and 1, which decreases with the improvement of mixing perfor-mance. For perfect mixing, XS = 0, and in a totally segregated med-ium, XS = 1.

Fig. 1 shows the experimental set-up. The diameter of the mi-cro-orifice was about 600 lm and perpendicular to the main chan-nel. The geometric size of the main channel was20 mm � 4 mm � 0.5 mm (length �width � height). Two reactantsolutions, diluted sulfuric acid solution (the dispersed solution) asFeed B and the solution containing KI, KIO3, NaH2BO3 and H3BO3

Fig. 2. Effect of feed flow rates and concentrations on the segregation index, particle size and Ca/P ratio of b-TCP nanoparticles: (a) H3PO4 0.1 mol/L, Ca(OH)2 1.01 mol/L,FD = 20 mL/min; (b) H3PO4 0.1 mol/L, Ca(OH)2 1.01 mol/L, FC = 120 mL/min; (c) H3PO4 1 mol/L, FC = 100 mL/min, FD = 20 mL/min; and (d) Ca(OH)2 1.01 mol/L, FC = 100 mL/min,FD = 20 mL/min.

L. Du et al. / Chemical Engineering Journal 221 (2013) 55–61 57

(the continuous solution) as Feed A were pumped into the microdevice and the parallel competing reaction was carried out tocharacterize the mixing performance. The triiodide complexformed in the micro device was detected at the outlet by UVspectrophotometry.

2.2. Preparation of b-TCP nanoparticles

Nanoparticles were produced in the micro-orifice dispersionmicroreactor, as shown in Fig. 1. In the preparation of b-TCP parti-cles, Ca(OH)2 suspension (0.135–1.35 mol/L) as the continuousfeed (Feed A) and H3PO4 aqueous solution (0.1–1 mol/L) as the dis-persed feed (Feed B) were mixed in the microreactor. The dispersedfeed was pressed through the micro-orifice into the microchannelto mix with the continuous feed coming from the continuous feedinlet. The two solutions were mixed in the microchannel and gen-erated CDHA, the precursor of b-TCP. To realize the complete reac-tion of Ca(OH)2, the suspension in the continuous feed wascirculated at a certain feed rate. At the beginning, the pH of the sys-tem was 12.3. The reaction process required 1–1.5 h for differentconditions and was stopped when the pH was 8.3. Then a ripeningtreatment stirring (200–400 r/m) in a beaker for 0.5–1 h was re-quired. All the procedures were processed at room temperature(�25 �C). Then the precursor precipitates were separated fromthe solution with a centrifugal separator (LD5-2A, Beijing MedicalCentrifugal Separator Factory). The prepared particles werewashed three times with distilled water, once with ethanol anddried in a drying cabinet at 100 �C for 24 h. Finally, the powderwas calcinated at 900 �C for 1 h to obtain b-TCP.

As a comparison, the preparation in a stirred tank reactor wascarried out. H3PO4 aqueous solution (0.1–1 mol/L) was slowlyadded dropwise (5–10 mL/min) into Ca(OH)2 suspension (0.135–1.35 mol/L) at room temperature in a 1000 mL beaker equippedwith a propeller agitator (1800 r/min). The reaction process re-quired 2–4 h for different conditions and was stopped when thepH was 8.3. The subsequent procedures such as ripening, separa-tion and calcination were the same to the microreaction.

The Ca/P molar ratio of the nanoparticles was measured by X-ray fluorescence spectrometry (Shimadzu Corporation). The mor-phology of the crystals was recorded by transmission electronmicroscopy (TEM; JEOL-2010 120 kV) images. And the crystal formof the particles was characterized by X-ray diffraction analysis(XRD; Rigaku Corporation D/max-RB). Fourier transform infraredspectroscopic measurements (FTIR; BRUKER Corporation TENSOR27) were taken to identify the molecular arrangement of theproducts.

3. Results and discussion

3.1. Characterization of the mixing performance

Fig. 2a and b shows the curves of the segregation index varyingwith the flow rates in the microreactor. The parallel competingreactions were also carried out in the stirred tank reactor to com-pare the segregation index. The value of XS in the microreactor wasonly 3–9% of that in stirred tank (XS = 0.142, the most efficient mix-ing condition), which exhibits better mixing performance. XS de-creases and Ca/P ratio increases with the increase of the

Fig. 3. Trends of pH value in the reaction.

58 L. Du et al. / Chemical Engineering Journal 221 (2013) 55–61

continuous solution flow rate, as shown in Fig. 2a. The increasedcontinuous feed flow rate provides a strong cross-flow shearingforce, which reduces the mixing scale, shortens the mass transferdistance [29]. The side reaction can be almost completely elimi-nated with efficient mixing process. Fig. 2b exhibits inconspicuouschange of XS, Ca/P ratio and particle size for the effect of the dis-persed solution flow rate.

With the efficient mixing process, the particles were preparedin a wide range of reactant concentrations and the synthesis washighly reproducible. The results are shown in Fig. 2c and d. Theconcentration of Ca(OH)2 and H3PO4 did not influence Ca/P ratiofor the efficient mixing. The b-TCP particle size distribution canbe varied from 80 nm to 120 nm at concentration of 0.1–1.5 mol/L. In addition, relatively high concentration of Ca(OH)2 avails sub-sequent particle growth and low concentration of H3PO4 is benefi-cial to reducing nucleus coating on Ca(OH)2 solid particle on thepreliminary stage. Compared with the traditional synthesis strate-gies of highly priced raw materials, relatively high temperatureand long reaction time, conditions are obviously improved by themicroreaction.

In the reaction process, pH value represents the mixing unifor-mity of the system. Fig. 3 shows the influence of mixing perfor-mance on pH value. The fluctuation of pH curves at higher XS

Fig. 4. TEM images of b-TCP nanoparticles: (a) H3PO4 0.1 mol/L, Ca(OH)2 1.01 mol/L, FC =FC = 120 mL/min, FD = 30 mL/min, XS = 0.0106; (c) H3PO4 1 mol/L, Ca(OH)2 1.01 mol/L,0.68 mol/L, FC = 40 mL/min, FD = 10 mL/min, XS = 0.0136.

demonstrated that H3PO4 excess took place locally, which gener-ated H2PO�4 and HPO2�

4 ions. Thus CaHPO4 particles with wide sizedistribution were generated and some of them remained insolubleuntil the synthesis process accomplished. The subsequent Ca/Panalysis proved the inference. Therefore, the operation is controlla-ble and the uniform reaction environment can be achieved withthe efficient mixing.

3.2. Structure and property analysis of b-TCP particles

b-TCP nanoparticles were prepared at efficient mixing condi-tions. Fig. 4 shows the TEM images of b-TCP particles, which exhi-bit that the particles are monodispersed and uniform in size. Theb-TCP particles are needle-shaped with a length and aspect ratioranged from 80 to 120 nm and 6 to 8, respectively. The size distri-butions of the particles are shown in Fig. 5, where num refers to thenumber fraction. These results show that the size distributions ofthe particles are relatively narrow at low XS value.

Crystal structures of the particles synthesized in the microreac-tor are shown in Fig. 6, given by the X-ray diffraction analysis. Thesharp crystalline peaks demonstrate highly crystalline b-TCP phasedue to the efficient mixing. In comparison, the crystal structures ofthe particles prepared at high XS conditions were of great differ-ence. The crystalline peaks of Ca2P2O7 are shown apparently, indi-cating Ca2P2O7 structure existing. Thus it was proven that sidereaction took place at inefficient mixing condition.

Fig. 7 shows the FTIR spectra of b-TCP nanoparticles. The FTIRspectra of b-TCP powders match well with the spectra reportedby others as well as with standard spectra [31,32]. The two pro-nounced absorption bands at 1031 and 1090 cm�1 and the twosharp peaks at 563 and 604 cm�1 arise from the PO3�

4 groups.The peaks at 563 and 1031 cm�1 are assigned to the bending andstretching vibrations of the PO3�

4 groups, respectively. In compari-son, the weak peak at 980 cm�1 indicates the presence of P2O4�

7 ,which also proves the b-TCP to be impure products for the higherXS conditions.

Table 1 shows the results of X-ray fluorescence spectrometry,which exhibit that Ca/P ratio of b-TCP nanoparticles. Apparently,Ca/P ratio and the content of b-TCP in the final products are in-creased with the decreasing of XS. The yield of b-TCP can be en-hanced up to 99.8%, about 33% larger than that of the products in

100 mL/min, FD = 20 mL/min, XS = 0.0098; (b) H3PO4 0.50 mol/L, Ca(OH)2 1.35 mol/L,FC = 120 mL/min, FD = 10 mL/min, XS = 0.0104; and (d) H3PO4 0.3 mol/L, Ca(OH)2

Fig. 5. Particle size distributions of b-TCP nanoparticles: H3PO4 0.3 mol/L, Ca(OH)2 1.01 mol/L. (a) XS = 0.142; (b) XS = 0.0162; and (c) XS = 0.0096.

Fig. 6. XRD patterns of b-TCP powders: H3PO4 0.3 mol/L, Ca(OH)2 1.01 mol/L. Fig. 7. FTIR spectra of b-TCP powders: H3PO4 0.3 mol/L, Ca(OH)2 1.01 mol/L.

Table 1Ca/P ratio and phase purity of b-TCP products.

Method Concentrations (mol/L) Synthesis conditions XS Ca/P Phase purity of b-TCP (%)

Batch reactor H3PO4 0.3 1800 r/m 0.142 1.332 66.4Ca(OH)2 1.01 5 mL/min (dropwise)

Microreactor H3PO4 0.3 FC = 20 mL/min 0.0162 1.371 74.2Ca(OH)2 1.01 FD = 20 mL/min

Microreactor H3PO4 0.3 FC = 60 mL/min 0.0110 1.426 85.2Ca(OH)2 1.01 FD = 20 mL/min

Microreactor H3PO4 0.3 FC = 20 mL/min 0.0096 1.499 99.8Ca(OH)2 1.01 FD = 120 mL/min

L. Du et al. / Chemical Engineering Journal 221 (2013) 55–61 59

Fig. 8. The concentration distributions of H3PO4, H2PO�4 , HPO2�4 and PO3�

4 ions.

60 L. Du et al. / Chemical Engineering Journal 221 (2013) 55–61

the tank. Thus it is convinced that the side reaction can be almostcompletely eliminated with efficient mixing process.

3.3. Mechanism analysis of the reaction

It is necessary to analyze the processes of reactions and masstransfer on the mechanism. x is introduced to quantify the molefraction of H3PO4, H2PO�4 , HPO2�

4 and PO3�4 , which is defined as:

xH2PO�4 ¼Ka1C2

Hþ

C3Hþ þ Ka1C2

Hþ þ Ka1Ka2CHþ þ Ka1Ka2Ka3

ð8Þ

xHPO2�4¼ Ka1Ka2CHþ

C3Hþ þ Ka1C2

Hþ þ Ka1Ka2CHþ þ Ka1Ka2Ka3

ð9Þ

xPO3�4¼ Ka1Ka2Ka3

C3Hþ þ Ka1C2

Hþ þ Ka1Ka2CHþ þ Ka1Ka2Ka3

ð10Þ

The pKa1, pKa2 and pKa3 of H3PO4 are 2.16, 7.21 and 12.32,respectively [33]. According to Eqs. (8)–(10), the concentrationdistributions of H2PO�4 , HPO2�

4 and PO3�4 are calculated at various

pH values, as shown in Fig. 8. With Ca(OH)2 suspension as theCa-source, pH value is kept at 12.3 at most of the time. Thus theconcentrations of HPO2�

4 and PO3�4 ions are almost equal. The gen-

Fig. 9. Schematic representation for the mechanism analy

eration of HPO2�4 accelerates the incorporation into the CDHA

structure. But the reaction of HPO2�4 with Ca2+ cannot be avoided.

Especially if CaHPO4 particles of relatively large particle size aregenerated, the converse reaction in Eq. (11) and reaction in Eq.(12) can hardly be achieved. Ca2P2O7 is finally obtained, which re-sults in Ca/P ratio <1.5 after the calcination.

Ca2þ þHPO2�4 $ CaHPO4 ð11Þ

HPO2�4 þOH� ! PO3�

4 þ H2O ð12Þ

Fig. 9 shows the tendencies of diffusion into aqueous solution ofHPO2�

4 and Ca2+ from solid CaHPO4 particles at different mixingconditions. For the inefficient mixing in the stirred tank, CaHPO4

particles are still generated and kept growing after H3PO4 is addedfor dozens of minutes and equivalently operated at around tentimes of the pipe length. The heterogeneous mixing and concentra-tion distribution causes CaHPO4 particles of large size generated,which result in slow diffusion of the reactant ions.

To avoid the inefficient mixing and generation of uneven-sizedCaHPO4 particles, it is feasible to enhance the mixing performanceand decrease the mixing scale with the microreactor. Fast and uni-form mixing are the apparent advantages of micro-structured de-vices. Complete mixing can be achieved in several millisecondsfor the homogeneous system [29]. Ca2+ ions are adequately con-tacted with PO3�

4 and the converse reaction in Eq. (11) is liable totake place owing to the efficient diffusion of HPO2�

4 and Ca2+ ionsfrom the relatively small crystal nucleus. Thus the mass transferprocess is significantly improved, which is available to enhancethe reaction (1). The related experiments also exhibit similarresults of desired Ca/P and uniform particle size.

4. Conclusion

A novel process using a microreaction to control the fast reac-tion process and the sizes and purity of b-TCP nanoparticles wassuccessfully developed. An efficient mixing and fast mass transferrate were achieved in the micro-orifice dispersion microreactor,leading to a uniform reaction environment and elimination of theside reaction with XS < 0.01. The observations of reaction processmonitor strongly provide the chemical information for the relationof Ca2þ;HPO2�

4 , PO3�4 with precursor CDHA and CaHPO4. The effects

of operation conditions on the particle sizes and Ca/P ration wereinvestigated, confirming that the nanoparticles preparation canbe controlled by the fast and uniform mixing. The size of b-TCPparticles fell in the range from 80 to 120 nm. The Ca/P molar ratio

sis of the reaction: (a) XS = 0.142 and (b) XS = 0.0096.

L. Du et al. / Chemical Engineering Journal 221 (2013) 55–61 61

b-TCP particles was in proximity to the theoretical value of 1.5. Thenew process with a fast microreaction can be easily scaled up,which has high potential in large scale application. In our futurework, it is necessary to understand the mechanisms of growth ofthe needle-shaped b-TCP nanoparticles and establish a theoreticalmodel.

Acknowledgements

We gratefully acknowledge the financial support of the NationalNatural Science Foundation of China (21036002) and SRFDP(20090002110070) on this work.

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