Supercritical-Assisted Atomization To Produce Micro - American

but in many other cases, the process was unsuccessful,2 probably as a result of ... mechanism: not only mixing but also release of gas from the liquid...
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Ind. Eng. Chem. Res. 2002, 41, 2405-2411

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Supercritical-Assisted Atomization To Produce Micro- and/or Nanoparticles of Controlled Size and Distribution E. Reverchon† Department of Chemical and Food Engineering, University of Salerno, Via Ponte Don Melillo, 84084 Fisciano (SA), Italy

A supercritical-assisted atomization (SAA) technique is proposed to produce micro- and nanoparticles of controlled size and distribution. It is based on the solubilization of controlled quantities of supercritical CO2 in liquid solutions containing a solid solute and on the subsequent atomization of the ternary solution through a nozzle. This technique has been successfully tested using some different kinds of compounds: superconductor and catalyst precursors, ceramics, and pharmaceutical compounds, using some different liquid solvents such as water, methanol, and acetone. As examples of this technique, nanometric and micrometric powders of zinc acetate, aluminum sulfate, zirconyl nitrate hydrate, sodium chloride, dexamethasone, carbamazepine, ampicillin, and triclabenzadol are proposed. A systematic analysis of the influence of the concentration of the liquid solution, kind of liquid solvent, and nozzle diameter on the particle size and distribution of SAA-produced powders is also proposed in the case of yttrium acetate micronization. Introduction Several supercritical fluids (SCFs) based techniques have been proposed to produce microparticles. They have been developed in an attempt to overcome the limits of traditional micronization techniques. Indeed, it is problematic, and in some cases impossible, to produce micronic or submicronic particles using jet milling, ball milling, and liquid antisolvent crystallization. The control of particle size (PS) and distribution (PSD) is approximate, and using liquid-solvent-based techniques, liquid residue remains in the solid matter. Carbon dioxide is the SCF of choice (SC-CO2) for these applications. It has been used in the rapid expansion of supercritical solutions. This process is based on the solubilization of the solid to be micronized in the SCF and its subsequent precipitation by fast depressurization of the formed solution. However, the use of this technique is largely limited by the low solubility in SCCO2 of many of the solids of interest.1 The supercritical antisolvent precipitation has also been proposed in various arrangements to perform micronization. This technique is based on the use of SCCO2 as the antisolvent to precipitate the solid solute from a liquid solution. The prerequisites for the success of this technique are the complete solubility of the liquid in the SCF and the complete insolubility of the solid in it.2,3 Several compounds have been successfully micronized down to mean PSs of 0.1 µm using this technique, but in many other cases, the process was unsuccessful,2 probably as a result of complex high-pressure vaporliquid equilibria (VLE) among the three components used for the process. Particle generation from gas-saturated solutions has also been proposed. In this case the product to be micronized is liquefied by heating and addition of SCCO2; then, the gas-liquid solution is sprayed in a lowpressure vessel, thus obtaining microparticles. This † Tel.: 039 089964116. Fax: [email protected].

039 089964057. E-mail:

technique has been successfully used1,4 to process several polymers but can have limited applicability in the case of thermolabile compounds that can decompose during the heating. Sievers and co-workers proposed the SC-CO2-assisted nebulization process5,6 that is based on the formation of a biphasic mixture of SC-CO2 and a water solution in a micrometric volume tee. The biphasic mixture is then sent to a capillary tube to form a spray in a atmospheric pressure precipitation chamber. The process was also patented.7,8 This last process seemed interesting to process watersoluble compounds that cannot be processed using the previously described techniques; therefore, we did some experiments in an apparatus similar to the one described by Sievers et al.5,6 Particularly, we used the near-zero-volume tee as suggested by Sievers and various kinds of capillary injectors (internal diameter d ) 125 µm and length L ) 5 cm, for example; therefore, L/d ) 400). However, we were not able to work in reproducible conditions probably because of the nonnegligible pressure drop inside the capillary tube and the consequent precipitation of part of the solute. The low-volume tee also allowed only an approximate mixing of the two streams. Therefore, we decided to perform supercriticalassisted atomization by adopting a substantially different process setup. We used a thermostated packed tower to obtain not only the mixing but also the equilibrium solubilization of CO2 in the liquid. The packed tower was designed to provide a contacting surface and a residence time sufficient to allow the dissolution of SCCO2 in the liquid solution up to the saturation conditions at the pressure and temperature of processing. Operating in this manner, we can also take advantage of a different and (we expect) more efficient atomization mechanism: not only mixing but also release of gas from the liquid droplets. Moreover, the liquid solution formed in the contacting device was sent to a thin wall injector to avoid the problem of capillary blockage. These experi-

10.1021/ie010943k CCC: $22.00 © 2002 American Chemical Society Published on Web 04/18/2002

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Figure 1. Schematic representation of the SAA apparatus: S1, inert gas heater; S2, S3, and S4, heat exchangers; P2 and P3, pumps; Sa, saturator; Pr, precipitator; Co, liquid condensator; C, dry test meter.

ments were immediately successful, using not only water but also organic solvents, and we obtained controlled micro- and nanoparticles. This supercriticalassisted atomization (SAA) process is described in this work together with its application to the micronization of some superconductor, ceramic, and catalyst precursors as well as to some pharmaceutical compounds. Experimental Apparatus Materials and Procedures The laboratory apparatus used for SAA is schematically reported in Figure 1. It mainly consists of three feed lines used to deliver SC-CO2, the liquid solution, and an inert gas and three main process vessels: saturator (Sa), precipitator (Pr), and condenser (Co). The CO2 line is arranged as follows: liquid CO2 from a cylinder is sent to a high-pressure pump (Gilson model 305) equipped with a dampener (Gilson model 805) to eliminate pressure oscillations; then, CO2 is sent to a heated bath (Forlab, Carlo Erba, TR12) and then to the contactor in which CO2 solubilizes into the liquid solution. The liquid solution is taken from a container, then is pressurized in a high-pressure pump (Gilson model 305), heated, and sent to the saturator. The inert gas is taken from a cylinder, sent to a calibrated rotameter (ASA model N5 2600), and heated in a heat exchanger (Watlow model CBEN 24G6). The saturator is a high-pressure vessel (internal volume of 50 cm3) loaded with stainless steel perforated saddles. The high surface packing has the scope of favoring the contact between CO2 and the liquid solution to obtain the dissolution of the gaseous stream in the liquid. The solid-liquid-gas solution at the exit of the contactor is sent to a thin wall injector (80 or 100 µm internal diameter). The injector was realized from a stainless steel cylinder (L ) 3 mm and D ) 15 mm); the first part of the hole is conical with an angle of 60° (L1 ) 2.2 mm); the second part is cylindrical (L2 ) 0.8 mm) and has been produced using a laser. Therefore, the ratio L2/d is in this case 8 or 10 depending on the values of d used; i.e., 40-50 times smaller than the capillary used by Sievers and co-workers.5-8 It produces a spray that forms the droplets in the precipitator. In the precipitator a flow of heated N2 is also delivered that has the scope of favoring the evaporation of the liquid solvent. The precipitator is a vessel operating at near-

atmospheric conditions built in stainless steel and has an internal volume of 3 dm3. The powder generated from the evaporation of the liquid droplets and the gas mixture formed by CO2 + nitrogen + liquid solvent vapors are forced to assume an ordinate motion inside the precipitator by a flux conveyor. This device consists of a helicoidal stainless steel device that occupies the entire section of the precipitator. The powder is then collected at the bottom of the precipitator on a stainless steel sintered frit (mean pore diameter of 0.1 µm), whereas the gases are discharged in a cooled condenser with the aim of condensating the liquid solvent; the resulting gas mixture (CO2 + nitrogen) is then sent to a dry test meter (Schlumberger model 2000AP LPG G2.5) to measure the overall flow rate. Calibrated thermocouples, manometers, check valves, high-pressure tubing, and connections complete the apparatus. Materials. Various materials have been micronized by SAA: yttrium acetate (AcY), purity 99.9%; sodium chloride (NaCl), purity 99.999%; zinc acetate, purity 99.99%; aluminum sulfate, purity 99.99%; zirconyl nitrate hydrate, purity 99%; carbamazepine (anticonvulsant drug), purity 99%; ampicillin trihydrate (antibiotic drug), purity 97%; triclabenzadol (antielmintic drug), purity 99%; dexamethasone (corticosteroid drug), purity 98%. They were all bought from Aldrich except triclabenzadol, which was kindly given by Virbac (Fr). Liquid solvents used to form the starting solution were as follows: methyl alcohol (MeOH), purity 99.99%; water, purity 99.99%; acetone, purity 99.99%. Analytical Methods. Compounds have been analyzed by high-performance liquid chromatography (HPLC; Hewlett-Packard model 1100 equipped with a C18 column) before and after the SAA process to ascertain their stability. Headspace gas chromatography (GC; Agilent model 6890 GC equipped with a 7694E headspace module) has been used to ascertain if solvent residues remained in the precipitated powder. X-ray diffraction (XRD) pattern analysis was performed using a Philips PW 1050 XRD apparatus to evaluate the crystallinity of the precipitated compounds. Samples of the powder precipitated on the metallic frit were observed by a scanning electron microscope (SEM; model LEO 420). SEM samples were covered with 250 Å of gold using a sputter coater (Agar model 108A). The PSs and PSDs were measured from SEM images using Sigma Scan Pro image analysis software (Jandel Scientific); about 1000 particle diameters were measured in the elaboration of each PSD. Experimental Results and Discussion The operative conditions that are characteristic of the SAA process are limited solubility between SC-CO2 and the liquid solvent and efficient contacting between the two phases (in the packed tower contactor). The first condition can be obtained by selecting the operating conditions (p and T). However, precise values of CO2 solubility under pressure in different liquids are available only for a limited number of CO2-liquid systems.9,10 Moreover, we want to solubilize CO2 in the liquid to perform the SAA process, but parallel to the increase of CO2 solubility in the liquid, also the solubility of the liquid in the fluid phase can increase. If the liquid massively solubilizes in the fluid phase, the

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Figure 2. VLE for the binary system MeOH-CO2 at 40 and 70 °C.

remaining liquid solution saturates and solid precipitation starts in the contactor. The second condition is obtained using a large contacting surface and adequate residence times in the contactor to obtain the saturation of the liquid with the compressed gas. The packed tower allows the equilibrium conditions to be obtained and continuous operation. Excess of CO2 with respect to the saturation can also be used. Indeed, as previously stated, CO2 solubility data in liquids under pressure are scarcely present in the literature. Because of the uncertainties in the solubility limits of CO2 in liquids under pressure, the possibility of operating with a moderate excess of SCCO2 ensures that the most favorable process conditions have been obtained. We resolved the process problems by (a) adding a moderate excess of CO2 with respect to the expected saturation concentration, (b) operating at pressures of a maximum 40 bar larger than the critical point, and (c) operating at relatively high temperatures in the saturator from 55 to 75 °C. The combination of these operating values ensures large CO2 solubility in the liquid (from 0.02 to 0.4 molar fraction) and relatively small liquid solubility in CO2. To explain this concept in Figure 2, the VLE diagram for the system MeOH-CO2 is reported at 40 and 70 °C. The experimental data at 40 °C were taken from the literature,11 whereas continuous curves were obtained using the Peng-Robinson equation of state:12 by interpolation at 40 °C and by extrapolation at 70 °C. From Figure 2 it is evident that when operating, for example, at 80 bar, the solubility of CO2 in methanol is near to complete miscibility at 40 °C and less than 0.4 at 70 °C, whereas the reverse solubility (of methanol in CO2) is in both cases small. This kind of information is only partly useful to evaluate the solubilities. Indeed, at this point, the question is, how does the presence of solute modify the binary liquid-CO2 equilibria? Information on this matter is presently missing, and we were obliged to do adjustments with respect to binary data, time by time, during the various series of experiments. A consequence of all of these considerations is that during SAA the operating pressure and temperature in the saturator have a limited flexibility because they are preset to optimize CO2 solubilization in the liquid solution. Examples of Morphologies Observed. The most frequently observed morphology during SAA is repre-

Figure 3. Amorphous spherical particles of AcZn precipitated from methanol at 102 bar, Tmix ) 85 °C, Tprecip ) 82 °C, and 80 mg/mL methanol.

Figure 4. Amorphous spherical particles of aluminum sulfate precipitated from water at 100 bar, Tmix ) 84 °C, Tprecip ) 75 °C, and 100 mg/mL water.

sented by spherical amorphous particles. Examples of this typology of particles are, for example, those obtained for zinc acetate precipitated by SAA from methanol at 102 bar, Tmix ) 85 °C, Tprecip ) 82 °C, and concentration of the solution ) 80 mg/mL and reported in Figure 3; the mean PS is lower than 0.5 µm. Similar morphologies were observed for aluminum sulfate precipitated from water. An example of this powder obtained at 100 bar, Tmix ) 84 °C, Tprecip ) 75 °C, and concentration of the solution ) 100 mg/mL is shown in the SEM image reported in Figure 4 characterized by a very narrow PSD of aluminum sulfate particles strictly ranging between about 1 and 2 µm; it also represents a good example of PS and PSD control obtained using SAA precipitation. Another SEM image of spherical amorphous particles is given in Figure 5, where zirconyl nitrate hydrate particles precipitated at 97 bar, Tmix ) 82 °C, Tprecip ) 76 °C from a water solution at 50 mg/mL and ranging between 1.5 and 3 µm are shown. In Figure 6 ampicillin particles precipitated from water (91 bar, Tmix ) 85 °C, Tprecip ) 64 °C, concentration ) 50 mg/mL) are shown that range between about 1 and 2 µm. In this case some small nanometric particles are also present. At last, dexamethasone submicron particles precipitated from acetone are shown in Figure 7. In this case the process conditions were 64

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Figure 5. Amorphous spherical particles of zirconyl nitrate hydrate precipitated from water at 97 bar, Tmix ) 82 °C, Tprecip ) 76 °C, and 50 mg/mL water.

Figure 6. Amorphous spherical particles of ampicillin precipitated from water at 91 bar, Tmix ) 85 °C, Tprecip ) 64 °C, 50 mg/mL water, and 100 µm injector.

Figure 7. Amorphous spherical particles of dexamethasone precipitated from acetone at 64 bar, Tprecip ) 81 °C, Tmix ) 72 °C, 6 mg/mL, and R ) 0.3.

bar, Tmix ) 72 °C, Tprecip ) 81 °C, and concentration of the solution ) 6 mg/mL. In all cases exemplified here, at low concentrations we observed the formation of nanoparticles and an increase of particle dimensions with the concentration of the liquid solution.

Figure 8. NaCl cubic crystals precipitated from water at 105 bar, Tmix ) 85 °C, Tprecip ) 80 °C, and different concentrations of (a) 5 and (b) 20 mg/mL water.

The formation of crystals was sometimes observed, for example, in the case of NaCl particles precipitated by SAA from water. In this case, as shown in parts a and b of Figure 8, cubic crystals were produced by operating SAA at 105 bar, Tmix ) 85 °C, Tprecip ) 80 °C, and concentrations of the liquid solution ranging from 5 to 20 mg/mL. The effect of the concentration of the water solution on NaCl crystals is clear from these figures: larger starting concentrations in the liquid solution produce larger crystals with sharper crystal surfaces (more regular crystals). In the case of carbamazepine precipitation from MeOH, crystals were also observed. In this case needlelike micronic crystals were obtained. Irregular crystals were also observed in the case of triclabenzadol precipitated by SAA from MeOH (Figure 9; process conditions are reported in the figure caption). For what concerns amorphous or crystalline particle formation, it seems related to the chemical nature of the solute and to its interactions with the liquid solvent. To the best of the present knowledge of SAA, the process parameters seem to have a negligible influence on the crystallinity of the powders produced. Chemical Analysis Performed on SAA-Produced Powders. Some kind of analysis was performed on SAA precipitates. The stability of the processed compounds was controlled by HPLC. This analysis is performed on

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Figure 9. Triclabenzadol irregular crystals precipitated from MeOH at 98 bar, Tmix ) 86 °C, Tprecip ) 75 °C, and 25 mg/mL.

Figure 10. Comparison of HPLC traces for untreated and SAAtreated dexamethasone.

the compound before and after SAA processing, and the changes in position, form, and dimensions of the peak measured at the outlet of the HPLC column give an indication of the modifications occurring in the processed compound. This analysis represents the standard method used by the pharmaceutical industry to control the stability of processed drugs. All tested compounds remained unchanged from the point of view of HPLC analysis when processed by SAA. An example of HPLC traces is reported in Figure 10 for dexamethasone precipitation from acetone. Untreated and SAA-processed dexamethasone show the same chromatographic characteristics. XRD analysis is commonly used to measure the crystallinity of a compound. As explained before, in many cases amorphous powders were obtained by SAA; in some other cases the crystalline pattern was retained. Headspace GC analyses were also performed on precipitated samples (except on those precipitated from water, of course) to control whether solvent residues remained in the processed powders. In all cases only some parts per million of solvent were found. Systematic Series of Experiments. Our studies on the SAA process were not limited to the analysis of particle morphology and physical charaterizations. We also performed some series of systematic experiments using the same solid compound (the superconductor precursor) AcY that was precipitated from water and from methanol at different starting concentrations of the liquid solution and using different injector diameters (80 and 100 µm). In all of the experiments performed in the following, the pressure and temperature in the

Figure 11. Amorphous spherical particles of AcY precipitated from water at 110 bar, Tmix ) 85 °C, Tprecip ) 70 °C, and (a) 5 and (b) 75 mg/mL water.

saturator were set at 110 bar and 80 °C, respectively. The temperature in the precipitator was set at 70 °C. Liquid solution flow rates were about 4.2 and 6.4 mL/ min for injector diameters of 80 and 100 µm, respectively. Nitrogen flow rates ranged between 50 and 60 Ndm3/min. SAA experiments were performed at various CO2liquid solvent ratios (R) ranging between 0.3 and 1.8 by weight. R ) 1.8 was used in the experiments performed using water and methanol, whereas R ) 0.5 was used in the experiments using acetone. These values of R correspond to the formation of a single binary phase between the liquid solvent and SC-CO2, except for the case of water in which also a second fluid phase is expected to be formed, but containing a nearnegligible content of water and solute. In the case of the organic solvents, the excess of CO2 with respect to the formation of a single liquid phase can adversely influence the performance of the process because of the formation of a nonnegligible quantity of a fluid phase that contains part of the solid solute. (i) AcY-H2O. Systematic experiments were performed on the system AcY-H2O at different concentrations of the solute and using the injector with a diameter of 80 µm. Two SEM images of AcY particles produced by SAA at low and high concentrations in water are reported in parts a and be of Figure 11 for 5 and 75 mg/mL solutions, respectively. Amorphous spherical particles

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Figure 12. PSDs of AcY powders precipitated from water at different starting concentrations in the liquid solution, based on the number of particles.

Figure 13. PSDs of AcY powders precipitated from water at different starting concentrations in the liquid solution, based on particle volume.

are formed. From these figures, it is also possible to qualitatively observe the effect of concentration: in Figure 11a the mean particle diameter is lower than 1 µm, and in the second case diameters range between 1 and 2 µm. The quantitative effect of the concentration on particle diameters was reported in Figures 12 and 13. Figure 12 is related to number of particle-based distributions that are approximatively log-norm (asymmetric) distributions, whose mode ranges from 0.25 to about 0.70 µm. A continuous enlargement of PSDs is also shown because of the presence of small particles and the increasing percentage of larger particles that arrive up to a maximum of about 3.5 µm. Figure 13 shows the same information in terms of the volume of particle-based PSDs. These kinds of distributions were practically Gaussian (symmetric), and the AcY mean PS on volume basis ranged from 0.75 µm at 5 mg/mL to 2.0 µm at 75 mg/mL. The volume-based PSDs enhance the contribution to the PSD of the larger particles with respect to the ones based on particle number. The simplest example of application of these kinds of distributions is given by the pharmaceutical industry in which the quantity of the compound delivered is the key parameter to indicate the therapeutic performance (dose-response indication).

Figure 14. Amorphous spherical particles of AcY precipitated from methanol at 110 bar, Tmix ) 80 °C, Tprecip ) 70 °C, and 31 mg/mL methanol.

Figure 15. PSDs of AcY powders precipitated from methanol at different starting concentrations in the liquid solution, based on particle volume.

(ii) AcY-MeOH. Systematic experiments at various concentrations of the liquid solution were also performed for the AcY-MeOH system, using an 80 µm injector. The observed morphology is the same as that observed for SAA precipitation of AcY from water. An example of SAA-precipitated AcY particles from methanol is shown in Figure 14: spherical amorphous particles have been obtained. The effect of concentration for this series of experiments is shown in Figure 15, where number of particle-based PSDs are reported. These distributions are again log-norm and, as espected, PS increases and PSD enlarges with concentration, confirming the previous observations. The mode of AcY particles ranges from less than 0.1 µm at 10 mg/mL to about 0.15 µm at 31 mg/mL. The comparison of experimental results obtained for SAA precipitation from water and methanol of the same compound (AcY) and in the same operating conditions shows that in the case of precipitation from methanol sharper PSDs were obtained when compared with those representing the precipitation from water. A more accurate observation of PSDs in Figures 12 and 15 shows that the major difference between the two series of PSDs is that in the case of SAA precipitates from methanol the larger particles of the distribution are not present: probably a more uniform distribution of the liquid droplets has been obtained during the atomization process.

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A series of SAA experiments using AcY-MeOH solutions was also performed using a 100 µm diameter injector to evaluate the possible effect of the injector diameter on the PS and PSD. Again the morphology was represented by spherical amorphous particles, and number of particle-based distributions were approximatively log-norm. Only slightly larger particles were obtained when compared to similar results obtained using the smaller injector, though the large injector has a section that is about 60% larger than the other one. As a result of all of the evidences collected until now on the SAA process, it is now possible to propose a mechanism of the atomization process that could explain the experimental results. The process is characterized by the formation of small droplets by atomization of the liquid in the thin wall nozzle (primary droplets) and by the probable subsequent formation of smaller droplets (secondary droplets) by droplet breakup due to the extremely rapid release of CO2 from the inside of the primary droplets (decompressive atomization). The formation of primary and secondary droplets is not new in atomization processes as described by Lavernia and Wu.13 What is really new is the formation of submicronic and micronic droplets at relatively mild conditions of pressure and temperature. The differences in results observed when we used different solvents can depend on the different strengths of cohesive forces operating on the formed droplets: surface tension and viscosity. Indeed, water and methanol at 20 °C show very similar viscosities, whereas the surface tension of water is about 3 times that of methanol at the same temperature condition. Even more important is the fact that the dissolution of a gas in a liquid strongly reduces the viscosity and the surface tension of the formed solution. The more is the quantity of dissolved gas, the more is the reduction of these cohesive forces.14 This information could be another key to explain the efficiency of the SAA process. Moreover, the most pronounced reduction of viscosity and surface tension is obviously obtained in the case of precipitation from methanol because at the process conditions, the solubility of CO2 in this solvent is much larger than that in water. Thus, smaller and more uniform droplets can be formed using methanol. Again, as for the high-pressure equilibria previously described, the influence of the presence of solute on the viscosity and surface tension of the solution is not known, but it is possible to suppose that the same solute can influence in the same manner the properties of the two liquids. Conclusions and Perspectives We developed and widely tested a general validity SCF-based technique that can be applied to many solvents and solutes. Controlled PSs and PSDs of micronic and submicronic particles can be obtained with modes ranging from about 0.1 to about 3.0 µm. The

process parameter that mainly controls PS resulted in the concentration of the liquid solution. No degradation has been observed even for pharmaceutical thermolabile compounds. The process is semicontinuous and easily scalable, and thus, it is suitable for the production of large quantities of micro- and nanopowders; for these reasons, it has also been patented.15 Acknowledgment The author acknowledges Dr. F. Lodato, A. Russo, A. Spada, R. Adami, and C. Volpe for their help in performing the SAA experiments reported in this work. Financial support from MIUR (Italian Ministry of Scientific Research) (PRIN 2000) is also acknowledged. Literature Cited (1) Jung, J.; Perrut, M. Particle design using supercritical fluids: Literature and patent survey. J. Supercrit. Fluids 2001, 20, 179. (2) Reverchon, E. Supercritical antisolvent precipitation of micro- and nano-particles. J. Supercrit. Fluids 1999, 15 (1), 1. (3) Reverchon, E.; Della Porta, G.; Pace, S.; Di Trolio, A. Supercritical Antisolvent Precipitation of Submicronic Particles of Superconductor Precursors. Ind. Eng. Chem. Res. 1998, 37, 952. (4) Weidner, E.; Steiner, R.; Knez, Z. Powder generation from polyethyleneglycols with compressible fluids. In High-Pressure Chemical Engineering; von Rohr, R., Trepp, Ch., Eds.; Elsevier: New York, 1996; p 223. (5) Xu, C.; Watkins, B. A.; Sievers, R. E.; Jing, X.; Trowga, P.; Gibbons, C. S.; Vecht, A. Submicron sized spherical yttrium oxide based phosphors prepared by supercritical CO2 assisted aerosolization and pyrolysis. Appl. Phys. Lett. 1997, 71 (12), 1643. (6) Sievers, R. E.; Karst, U.; Milewski, P. D.; Sellers, S. P.; Miles, B. A.; Schaefer, J. D.; Stoldt, C. R.; Xu, C. Y. Formation of Aqueous Small Droplet Aerosols Assisted by Supercritical Carbon Dioxide. Aerosol Sci. Technol. 1999, 30, 3. (7) Sievers, R. E.; Karst, U. Methods and apparatus for fine particle formation. U.S. Patent 5639441, 1997. (8) Sievers, R. E.; Sellers, S. P.; Carpenter, J. F. Supercritical fluid-assisted nebulization and bubble drying. WO Patent 00/ 75281, 2000. (9) Ohe, S. Vapor-Liquid Equilibrium Data at High Pressure; Elsevier: Amsterdam, The Netherlands, 1990. (10) Kordikowski, A.; Schenk, A. P.; Van Nielen, R. M.; Peters, C. J. Volume expansions and vapor-liquid equilibria of binary mixtures of a variety of polar solvents and certain near-critical solvents. J. Supercrit. Fluids 1995, 8, 205. (11) Ohgaki, K.; Katayama, T. J. Chem. Eng. Data 1976, 21, 531. (12) Peng, D.-Y.; Robinson, D. B. A new two-constant equation of state. Ind. Eng. Chem. Fundam. 1976, 15, 59. (13) Lavernia, E. J.; Wu, J. Spray Atomization and Deposition; Wiley: New York, 1996. (14) Brunner, G. Gas Extraction; Springer-Verlag: New York, 1994. (15) Reverchon, E. Process for the production of micro and/or nano particles. Swiss Patent 1209/01, 2001.

Received for review November 27, 2001 Revised manuscript received March 1, 2002 Accepted March 5, 2002 IE010943K