The Preparation of Spherical Calcium Phosphate Fine Particles Using

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Langmuir 2000, 16, 955-960

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The Preparation of Spherical Calcium Phosphate Fine Particles Using an Emulsion Liquid Membrane System Takayuki Hirai,* Masayuki Hodono, and Isao Komasawa Department of Chemical Science and Engineering, Graduate School of Engineering Science, Osaka University, Toyonaka 560-8531, Japan Received May 17, 1999. In Final Form: September 16, 1999 Calcium phosphate fine particles were prepared by using an emulsion liquid membrane (ELM, waterin-oil-in-water (W/O/W) emulsion) system, consisting of Span 83 (sorbitan sesquioleate) as surfactant and VA-10 (2-methyl-2-ethyl heptanoic acid) as extractant (cation carrier). Calcium ions were extracted from the external water phase and stripped into an internal water phase containing phosphate anions, to form calcium phosphate particles. The submicrometer-sized spherical calcium phosphate particles obtained were characterized by scanning electron microscopy (SEM), powder X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectrophotometry and thermal analysis (TG-DTA). The characterization revealed that the fine particles obtained were calcium-deficient apatite in combination with various other calcium phosphate species. Decomposition from hydroxyapatite to β-TCP (whitlokite) occurred at 973 K, and thermal treatment above 1073 K produced a β-TCP and CaO composite. The freeze-thaw demulsification method yielded well-defined spherical particles of 0.5-20 µm (mostly smaller than 10 µm) in diameter; the shape and size of the internal water droplets is likely to influence the morphology of the formed particles.

Introduction An emulsion liquid membrane (ELM, water-in-oil-inwater (W/O/W) emulsion) system has been studied for the selective separation of metals, in which the metal ions in the external water phase are extracted into the organic membrane phase, and then stripped and concentrated into the internal water phase. Recently, it has been found that the internal water phase is capable of being used for the preparation of size-controlled and morphologycontrolled fine particles, since the micron-sized internal water droplet has a restricted reaction area. In addition, since the ELM system has a high selectivity, purification and preconcentration of the target metals are not needed. The preparation of other fine particles, such as the precious metal particles,1 copper oxalate particles,2,3 rare-earth oxalate spherical particles,4,5,6 calcium carbonate particles,7,8 using the ELM system has been reported extensively. Calcium phosphates constitute the major constituent of bone, and hold great promise as a potential biomaterial for bone implantation since they have the ability to bond to bone. Hydroxyapatite is the main mineral constituent of natural bone, and thus synthetic calcium phosphate ceramics such as hydroxyapatite and β-TCP (β-Ca3(PO4)2) may create an excellent bond with natural tissue and may * Correspondence concerning this article should be addressed to T. Hirai (E-mail: [email protected]). Tel: +81-6-68506272. Fax: +81-6-6850-6273. (1) Majima, H.; Hirato, T.; Awakura, Y.; Hibi, T. Metall. Trans. B 1991, 22B, 397-404. (2) Yang, M.; Davies, G. A.; Garside, J. Powder Technol. 1991, 65, 235-242. (3) Hirai, T.; Nagaoka, K.; Okamoto, N.; Komasawa, I. J. Chem. Eng. Jpn. 1996, 29, 842-850. (4) Hirai, T.; Okamoto, N.; Komasawa, I. AIChE J. 1998, 44, 197206. (5) Hirai, T.; Okamoto, N.; Komasawa, I. J. Chem. Eng. Jpn. 1998, 31, 474-477. (6) Hirai, T.; Okamoto, N.; Komasawa, I. Langmuir 1998, 14, 66486653. (7) Davey, R. J.; Hirai, T. J. Cryst. Growth 1997, 171, 318-320. (8) Hirai, T.; Hariguchi, S.; Komasawa, I.; Davey, R. J. Langmuir 1997, 13, 6650-6653.

even stimulate new bone growth. Hydroxyapatite and β-TCP ceramics are widely applied nowadays to coat artificial joint and tooth roots.9 Plasma spray is a widely employed process to deposit the calcium phosphate coating on the implant. The required characteristics of the feed powder for the plasma-spraying process are spherical morphology and a narrow particle size range.10 Spherical morphology is needed to enhance the flowability of the powder feedstock from the powder hopper to the plasma spray gun and a narrow particle size range ensures that all the species in the plasma spray remain at the same physical state. In addition, the powder should be completely molten, but not superheated, in the plasma flame. In this work, the ELM system is used in order to prepare calcium phosphate fine particles having spherical morphology and narrow particle size range and therefore high suitability for plasma spray coating applications. Experimental Section VA-10 (2-methyl-2-ethyl heptanoic acid), supplied by Shell Chemical Co., and sorbitan sesquioleate (Span 83), supplied by Tokyo Kasei Kogyo Co., Ltd., Tokyo, Japan, were used in all experiments as extractant and surfactant, respectively. Equal volume quantities of the internal water phase of the emulsion (aqueous solution of 0.05 mol/L H3PO4 (pH ) 2-3) or 0.1 mol/L Na2HPO4 (pH ) 8-9)) and the organic membrane phase (kerosene containing 0.5 mol/L VA-10 and 8 wt % Span 83) were mixed together and emulsified by use of a mechanical homogenizer (12 000 rpm). The resulting W/O emulsion (10 mL) was poured into the external water phase solution (50 mL of 0.005-0.01 mol/L Ca(NO3)2 and 0.1 mol/L NH3) and stirred vigorously to form the W/O/W emulsion, used to extract Ca2+ ions and form calcium phosphate particles. The size of the W/O emulsion drops dispersed in the external water phase was less than 2 mm in diameter. The feed molar ratio concentration, (Ca/P)f, in most cases was kept at (Ca/P)f ) 1.0, which means that the external water phase solution (50 mL) contains 0.005 mol/L Ca(NO3)2 and that the internal water phase (5 mL) solution contains 0.05 mol/L H3PO4. Varying the (Ca/P)f ratio was used to study its (9) de Groot, K. J. Ceram. Soc. Jpn. 1991, 99, 943-953. (10) Khor, K. A.; Cheang, P. J. Mater. Process. Technol. 1997, 63, 271-276.

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effect on the resultant Ca/P molar ratio of the particles, (Ca/P)p. In this case, the PO43- concentration of the internal water solution was fixed at 0.05 mol/L. After stirring 2 h, except for cases employing a freeze-thaw demulsification method, the W/O/W emulsion was then left to allow the W/O emulsion to separate from the external water phase. The resulting upper emulsion phase was washed with distilled water, followed by centrifugation (1000 rpm) to remove the external water phase. The W/O emulsion was then demulsified either by adding 40 mL ethylene glycol or by use of a freezethaw method, in which the emulsion was completely frozen at 188 K for 24 h and then thawed at 298 K.7,8 Subsequent centrifugation produced three phases: oil as the upper phase, water as the lower phase, and a small amount of emulsion at the organic-aqueous interface, containing most of the particles. After the transparent upper and lower phases were removed, the remaining emulsion phase was washed with ethanol, and the particles obtained were vacuum-dried following a prior centrifugation. To study their sintering behavior, the prepared particles were heated in air, in the temperature range 873-1273 K and with soaking times of 2 h at a rate of 10 K/min up to peak temperature. The heated samples were then furnace cooled to ambient temperature. The particles formed were characterized by means of scanning electron microscopy (SEM) (Hitachi S-5000), powder X-ray diffraction (XRD) (40 kV-30 mA, Cu KR, Philips PW-3050), Fourier transform infrared (FTIR) spectrophotometry (Jasco FT/ IR-610) and thermal analysis (TG-DTA) (Shimadzu TG-DTA50). Prior to SEM examination, all the samples were sputter-coated by a ca. 10 nm thick platinum layer, to minimize any possible surface charging effects. A laser scattering particle-size distribution analyzer (HORIBA LA-910W) was used for measuring the size of the internal aqueous droplets. The concentrations of Ca2+ in the external water phase, the organic membrane phase, and (Ca/P)p were determined using an inductively coupled argon plasma atomic emission spectrometer (ICP-AES) (Nippon JarrellAsh ICAP-575 MarkII). To assay the quantity of Ca2+ ions remaining in the organic membrane phase, the W/O emulsion was demulsified electrically and the organic phase was stripped with 1 mol/L HCl solution. The Ca2+ concentration was then measured. Ca2+ concentrations in the internal water phase were calculated by mass balance. Control experiments were carried out using a homogeneous aqueous solution (obtained by mixing simply the feed aqueous solutions) in order to compare the results with those for the products of the ELM system.

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Figure 1. Time-course variation for mole percent compositions of Ca2+ ions in the external water phase, organic membrane phase, and internal water phase of the ELM system at (Ca/P)f ) 1.0.

Results and Discussion Extraction Behavior of Ca2+ Ions. The extractive ability of carboxylic acid type extractants for metal ions is weaker than that of extractants of the organophosphorus type.11 Liquid-liquid extraction studies of Ca2+ ions indicated that the half-extraction pH, pH1/2, value for the extraction of calcium using VA-10 was about 7, at the conditions as used in the ELM system. The transport of calcium ions into the internal water phase can therefore be achieved by adjusting the initial pH value of the external water phase higher than the pH1/2 and that of the internal water phase lower. Figure 1 shows the variation in the mole percent concentration of the Ca2+ ions in the external water phase, the organic membrane phase, and the internal water phase in the ELM system as a function of time, with the results showing that the transport of calcium ions into the internal water phase is completed in 30 min, and only a small quantity of the calcium ions (ca. 2-3%) is retained in the organic phase. Thus, almost all the calcium ions were transported successfully into the internal water phase. Characterization of Calcium Phosphate Particles Obtained in ELM system. Calcium phosphate fine particles are precipitated, following the extraction of calcium ions from the external phase into the internal (11) Preston, J. S. Hydrometallurgy 1985, 14, 171-188.

Figure 2. Scanning electron micrographs for calcium phosphate prepared at (Ca/P)f ) 1.0 in (a) the ELM system and (b) homogeneous aqueous solution.

phase. The SEM image of the particles obtained at (Ca/P)f ) 1.0 in the ELM system is shown in Figure 2a, thus demonstrating that submicrometer-sized spherical fine particles (0.1-0.3 µm in diameter) were obtained. In the homogeneous aqueous solution under a similar concentration condition and reaction time, on the other hand, smaller precipitates were obtained which were not spherical and which were irregularly coagulated, as shown in Figure 2b. The internal water phase, therefore, is capable of being used for the preparation of size and morphology

Spherical Calcium Phosphate Prepared Using ELM

Figure 3. Time-course variation for the diameter distribution of the internal water droplets at (Ca/P)f ) 1.0.

Figure 4. X-ray diffraction patterns for calcium phosphate prepared at (Ca/P)f ) 1.0 in (a) the ELM system and (b) homogeneous aqueous solution.

controlled fine particles, as is also the case for spherical rare-earth-metal oxalates.4,6 The precipitates obtained in the ELM system and in the homogeneous solution are, however, smaller than the internal droplet size, which ranged from 0.1 to 10 µm, as shown in Figure 3. The XRD measurements, as shown in Figure 4a and 4b, demonstrate that the submicrometer-sized spherical particles obtained in the ELM system are amorphous, while the precipitates in the homogeneous solution show diffraction peaks of hydroxyapatite with low crystallinity. Although hydroxyapatite is thermodynamically the most stable species of calcium phosphate salt, other species such as dicalcium phosphate dihydrate (CaHPO4‚2H2O) and amorphous calcium phosphate are formed during the first stages of calcium phosphate precipitation in aqueous solutions. As the transformation of amorphous calcium phosphate to hydroxyapatite proceeds, via dissolution of the amorphous calcium phosphate in aqueous solution, to form hydroxyapatite, it is necessary for calcium phosphate precipitates to be soaked for a few weeks in a water-rich solution.12 This suggests that the spherical calcium phosphate particles obtained in the internal aqueous droplets are precipitated under a deficiency of water condition. In previous work,4,5,6 rare earth metal oxalate fine particles, obtained in the ELM system, were demonstrated to have no characteristic XRD peak and have a lower hydration number. The internal water phase of the ELM system, therefore, seems to be rather hydrophobic. The precipitation reaction for Ca2+ and PO43- may occur mainly at sites which are near or in contact with the (12) Lerner, E.; Azoury, R.; Sarig, S. J. Cryst. Growth 1989, 97, 725730.

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Figure 5. FTIR spectra for (a) calcium phosphate fine particles prepared at (Ca/P)f ) 1.0 by the ELM system and (b) hydroxyapatite reference material.

oil-internal water solution interface. The precipitation reaction in the internal aqueous droplets, therefore, behaves as if there were not much water in the internal water phase. Figure 5 shows that the FTIR spectrum for the spherical particles prepared in the ELM system is similar to that of the spectrum of the commercial hydroxyapatite. The peak at ca. 870 cm-1 can be ascribed mostly to the HPO42group, but no absorption peak corresponding to the OHgroup (at 3574 cm-1) appears for the particles prepared in the ELM system. The absorption bands, in the range of 560-610 and 930-1100 cm-1, derived from PO43-, are weaker than those for commercial hydroxyapatite. It is generally accepted that the peak intensity and sharpness of these absorption bands are indications of the degree of crystallinity. For example, crystallinity can be judged from the characteristic peak splitting at 565 and 606 cm-1, and the peak splitting at 1100 and 967 cm-1 derived from the peak at 1040 cm-1 owing to PO43-.12 The FTIR spectrum shows, therefore, that the spherical particles obtained by the ELM system are hydroxyapatite of low crystallinity. The phase constitution and chemical homogeneity of the particles were further examined by quantitative chemical analysis, employing dissolution of the particles using 1 mol/L HCl and ICP-AES analysis. The Ca/P atomic ratio of the particles prepared at (Ca/P)f ) 1.0 in the ELM system was determined as 1.29. This value is lower than the stoichiometric molar ratio for hydroxyapatite (Ca/P)p ) 1.67. The lower Ca/P ratio and the absence of the absorption peak in the FTIR spectrum (Figure 5) equivalent to OH- incorporation show that the particles are calcium-deficient apatite, with additional phases such as amorphous calcium phosphate or octacalcium phosphate and incorporating various combination lattice defects.14 However nonstoichiometry derived from the presence of CO32- incorporated in the lattice was rather ignorable. There is a strong band for commercial hydroxyapatite, but scarcely anything for the ELM precipitate, as shown by the absorption band at 1400-1500 cm-1 in Figure 5. These results of the characterization, therefore, show that the submicrometer-sized spherical particles obtained in the ELM system are calcium-deficient apatite with other coexisting calcium phosphate species. An amorphous calcium phosphate is generally composed of calciumdeficient hydroxyapatite, phosphate species adsorbed on the surface, additional calcium phosphate phases, and various lattice defect combinations.13,14 Since the necessary (13) Suchanek, W.; Suda, H.; Yashima, M.; Kakihana, M. J. Mater. Res. 1995, 10, 521-529. (14) Li, J.; Liao, H.; Sjo¨stro¨m, M. Biomaterials 1997, 18, 743-747.

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Figure 6. Scanning electron micrographs for calcium phosphate fine particles prepared at (Ca/P)f ) 1.0 in the ELM system, following calcination for 2 h at temperatures of (a) 873 K, (b) 973 K, (c) 1073 K, and (d) 1273 K.

powder characteristics favored in plasma spraying are those of spherical morphology and narrow particle size range,10 the particles prepared in the ELM system are, therefore, adequate as feed material for the plasmaspraying process. Thermal Analyses of Particles. Calcination of the particles was performed to study the thermal behavior of the submicrometer-sized spherical particles. In this, the particles prepared at (Ca/P)f ) 1.0 by the ELM system were calcined, and the resultant particles were characterized by use of SEM and XRD. The SEM images for the particles, following calcination, are shown in Figure 6. No significant change in the size and morphology of the particles is apparent for calcination temperatures below 873 K. After calcination above 973 K, however, the sintered particles became greater in size (e2 µm). The particles sintered at each temperature level were characterized by XRD, as shown in Figure 7. Below 873 K the particles are amorphous. Some peaks appear at 973 K, and the calcination of particles above 1073 K produces the characteristic patterns of β-TCP (β-Ca3(PO4)2, whitlockite), coincident with the peaks of CaO (at 32.1° and 37.3°). Similar XRD results were obtained for the precipitates prepared in the homogeneous system, excepting the case of the weak hydroxyapatite below 873 K. Thus, particles obtained by calcination above 973 K are composites of β-TCP and CaO. Figure 8 shows the results of TG-DTA analysis, obtained for the spherical calcium phosphate particles. An endothermic peak corresponding to dehydration occurs at ca.

Figure 7. X-ray diffraction patterns for calcium phosphate fine particles prepared at (Ca/P)f ) 1.0 in the ELM system, before and following calcination for 2 h at each temperature.

373 K. An exothermic peak at ca. 973 K is also shown, which by consideration of the result of the XRD analysis corresponds to the decomposition of hydroxyapatite to β-TCP. It is reported that this decomposition occurs according to the reaction15,16

Ca10(PO4)6(OH)2 w 3Ca3(PO4)2 + CaO + H2O and is accompanied only by a 1.8% weight loss and is difficult to detect precisely via thermogravimetric analysis.

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Figure 8. TG-DTA curve for calcium phosphate fine particles prepared at (Ca/P)f ) 1.0 in the ELM system.

Figure 9. Relationship between the Ca/P molar ratio for spherical calcium phosphate particles prepared in the ELM system, (Ca/P)p, and the feed molar ratio, (Ca/P)f. The (Ca/P)p value 1.67 corresponds to the stoichiometric value for hydroxyapatite.

Figure 10. IR spectra for the particles prepared at various (Ca/P)f values in the ELM system.

Since however a 1.1% weight loss at 973 K was observed, the particles prepared in the ELM system should contain more than 50 wt % hydroxyapatite. Relationship Between (Ca/P)f and (Ca/P)p. Increasing the value of (Ca/P)f increases the value of the Ca/P molar ratio of the particles, (Ca/P)p, obtained, as shown in Figure 9. For cases of (Ca/P)f greater than 1.6, however, the value of (Ca/P)p becomes almost saturated at ca. 1.50. (15) Kivrak, N.; Tas, A. C. J. Am. Ceram. Soc. 1998, 81, 2245-2252. (16) Arends, J.; Christoffersen, J.; Christoffersen, M. R.; Eckert, H.; Fowler, B. O.; Heughebaert, J. C.; Nancollas, G. H.; Yesinowski, J. P.; Zawacki, S. J. J. Cryst. Growth 1987, 84, 515-532.

Figure 11. Scanning electron micrographs for calcium phosphate particles, prepared at (Ca/P)f ) 1.0 in the ELM system via demulsification using the freeze-thaw method after 1 h stirring. (a) as prepared and (b) and (c) cross sectional views.

This occurs since the percentage extraction for Ca2+ is reduced as the feed Ca2+ concentration in the external water phase is increased. Figure 10 shows the FTIR spectra for particles prepared at various (Ca/P)f values, where it can be seen from the absorption band (560-610 and 930-1100 cm-1), that the crystallinity of the particles decreases with increasing (Ca/P)f ratio. XRD measurement also showed that the particles prepared at (Ca/P)f values greater than 1.2 were amorphous.

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In the case of wet chemical methods, high pH is usually preferable in the preparation of stoichiometric hydroxyapatite. As shown in Figure 9, when using disodium hydrogenphosphate (Na2HPO4, pH ) 8-9) as the internal water phase at (Ca/P)f ) 2.0, the (Ca/P)p of the resulting particles was higher than that obtained using phosphoric acid (H3PO4, pH ) 2-3). However, the XRD and FTIR analyses also reveal that the crystallinity of the particles, when prepared by using Na2HPO4 solution as the internal water droplets, is also amorphous. Further investigations based on the Na2HPO4 solution appear to be difficult, since the ELM system when prepared at other (Ca/P)f values is unstable. Previous study has reported that the Ca/P molar ratio increases with increasing pH of solution.13 Several interpretations of this phenomenon have been proposed. At lower pH, hydroxyapatite often becomes less stable than dicalcium phosphate.17 Another explanation is possible since in H3PO4 solution, the PO43- ions dominate only above pH ) 12 and at lower pH there is a large excess of protonated phosphate ions (H2PO4-, HPO42-) in the mother liquor.13 Particles prepared under a more acidic condition therefore have a lower Ca/P molar ratio in comparison with those prepared using Na2HPO4. The Freeze-Thaw Demulsification Method. When ethylene glycol is used as the demulsifying agent and the calcium phosphate particles are separated immediately from the emulsion, spherical particles of mainly submicrometer size are observed, as shown in Figure 2a. In contrast, the freeze-thaw demulsification following 1 h stirring yields well-defined spherical particles having a relatively wide size distribution in the range 0.5-20 µm (mostly smaller than 10 µm) diameter, as shown in Figure 11a. Characterization using XRD, FTIR, and ICP-AES showed that these particles have the same properties as the submicrometer-sized ones, when prepared under equal conditions. The SEM images based on the cross-sections of micrometer-sized spherical particles, buried in an epoxy resin and sliced with a rotary microtome, are given in Figures 11b and 11c. These show that the smaller particles have a fully packed structure, whereas the larger particles have a hollow, shell-like morphology, as also occurs in the case of calcium carbonate.8 (17) Boistelle, R.; Lopez-Valero, I. J. Cryst. Growth 1990, 102, 609617.

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Since the particle size range is comparable to that of the size distribution for the internal water droplets (Figure 3), during the freezing stage the submicrometer-sized particles are likely to slowly aggregate together to form micrometer-sized particles. The droplet size distribution, however, is shifted toward the larger diameter region and maximum size reaches 40 µm after 2 h stirring, owing to the aggregation of the internal water droplets. Reflecting this, the freeze-thaw demulsification, after 2 h stirring for various (Ca/P)f, yields both submicrometer-sized particles and irregularly shaped aggregates of 20-100 µm in diameter. In the freeze-thaw demulsification method, therefore, the shape and size of the internal water droplets is likely to influence the morphology of the formed particles. Conclusion Submicron-sized spherical calcium phosphate fine particles were obtained by the application of an emulsion liquid membrane system, and were found to consist of a calcium-deficient apatite with various combinations of other calcium phosphates species, using XRD, FTIR, ICPAED, and TG-DTA analysis. Thermal decomposition of the resulting calcium phosphate to β-TCP occurred at 973 K. The molar composition of the formed particles, (Ca/P)p, was found to be controllable by varying the feed Ca/P ratio, (Ca/P)f. An increase of (Ca/P)f is, however, not accompanied by an improvement in the crystallinity. The freeze-thaw demulsification method yielded well-defined spherical particles, which had a relatively wide size distribution in the range 0.5-20 µm (mostly smaller than 10 µm) in diameter and having otherwise identical properties to the submicrometer-sized particles. Acknowledgment. The authors are grateful to the Division of Chemical Engineering, Department of Chemical Science and Engineering, Osaka University, for scientific support with respect to the “Gas-Hydrate Analyzing System (GHAS)” constructed by supplementary budget of 1995, and to financial support through Grantsin-Aid for Scientific Research (Nos. 09650829 and 11650781) from the Ministry of Education, Science, Sports and Culture, Japan. LA990590I