Producing Nanoparticles Using Precipitation with Compressed

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Ind. Eng. Chem. Res. 2007, 46, 3580-3589

MATERIALS AND INTERFACES Producing Nanoparticles Using Precipitation with Compressed Antisolvent Candy Lin and Ka Ming Ng* Department of Chemical Engineering, The Hong Kong UniVersity of Science and Technology, Clear Water Bay, Hong Kong

Christianto Wibowo ClearWaterBay Technology, Inc., 4000 W. Valley BouleVard, Suite 100, Pomona, California 91789

The application of supercritical fluid processing in pharmaceutical research is increasing, particularly in the field of particle formation for drug delivery systems, mainly due to advantages over the conventional particle formation in terms of improved control, flexibility, ease of operation, and level of toxicity from the presence of organic solvents and contaminants. Particle formation of salicylic acid using supercritical carbon dioxide (CO2) was investigated using the precipitation with compressed antisolvent (PCA) technique using ethanol and acetone as solvents. The solubility of salicylic acid (SA) in supercritical CO2 was measured in its pure form and with modifiers, at 45 and 55 °C over a pressure range of 95-250 bar. The output of the study gave promising conditions in particle formation by adjusting parameters based on the phase diagram obtained. Particles in the nanorange can be produced in the higher supersaturation region without changing the nozzle size of the PCA system. All the experimental conditions investigated here gave an average particle size of approximately 100 nm, with the smallest average particle size of 63.35 nm achieved by using 1% acetone modifying condition at 45 °C. The largest average particle size produced was 102.75 nm at the condition with 1% ethanol operating under a temperature of 55 °C. A dissolution experiment was also carried out to show significant improvement of drug dissolution rate with the smaller particle size. Introduction Particle design is becoming one of the main features in the production of pharmaceuticals, food, cosmetics, and other specialty chemical products. The final product performance can be greatly affected by particulate characteristics such as average particle size, size distribution, and morphology. This is particularly important for a large portion of newly emerging drugs, whose water-insolubility causes poor bioavailability and, thus, deserted drug development research efforts. By re-engineering these drug particles to be in the nanorange size, the solubility problem would be overcome.1,2 Not only would this solve solubility and stability issues, it would also minimize druginduced side effects due to the reduction of required drug dosages.3 Controlled drug particle attributes improve drug targeting, controlled drug release, solubility, and bioavailability.4-6 Because drug particles in the nanorange possess completely different properties than larger particle sizes, the drug effectiveness is greatly enhanced, including higher dissolution rate, improved absorption through gastrointestinal (GIT) wall, and greater adhesion when compared to microparticles. However, precise control means in the production of these particles are required to ensure quality particle product. A variety of methods have been developed for the production of nanoparticles, and the use of supercritical fluids is one of the more focused ones for drug and bioproduct processing. * To whom correspondence should be addressed. Tel.: +8522358-7238. Fax: +852-2358-0054. E-mail: [email protected].

Supercritical carbon dioxide (CO2) is of special interest because of its relatively low cost and environmentally benign properties. Its mild supercritical conditions (TC ) 31.1 °C and PC ) 73.8 bar) also offer easy access to the supercritical range during operation. Supercritical fluids have liquidlike densities and higher diffusivities than gases, which give an advantage in the ease of operation by altering pressure to achieve enhanced efficiencies. Supercritical fluids are explored as a potential solvent media for various separation and crystallization processes, which present great potentials in the pharmaceutical processing industry for the requirement of toxic and organic solvent-free products. Various studies have shown that supercritical CO2 can be used as a replacement for traditional organic solvents in various industrial processes.7 Precipitation with compressed antisolvent (PCA) using supercritical CO2 is one of the more investigated processes that have attracted a vast amount of attention in producing fine particles. A particular advantage of using the PCA technique is that not only are the particles formed organic solvent-free but also no further purification or separation in solvent removal is required in the formation of powdered blends, thin films, and microcapsules. A variety of chemicals have been precipitated from this PCA process such as explosives, polymers, pharmaceuticals, and coloring materials. However, a thorough understanding and knowledge of the solubility of the compound of interest in supercritical fluids is required for all applications of supercritical fluid related technologies. Conventional particle formation techniques tend to focus on the effect of different process parameters on the antisolvent

10.1021/ie0611204 CCC: $37.00 © 2007 American Chemical Society Published on Web 04/27/2007

Ind. Eng. Chem. Res., Vol. 46, No. 11, 2007 3581

Figure 1. Schematic diagram of the PEA equipment.

Figure 2. Schematic diagram of the PCA equipment.

precipitation process but do not offer much knowledge on the quantitative aspects of the process. Parameters that are frequently studied in observing the change in particle size and morphology include pressure, temperature, and flow ratios in the PCA process. However, different conclusions are drawn as some groups have observed significant changes in altering temperature and others pressure and flow ratios. Some have argued that particle attributes are to be affected by thermodynamics, while others believe kinetics is the control for particle design.8 Much work has also been focused on using jet hydrodynamics and atomization theory as a guide for manipulating and controlling particle size during the PCA process.9 The mixing effect of a variety of designed nozzles gave rise to a new area of study in the formation of fine initial liquid droplets and, hence, fine particle formation. Despite significant progress in these directions, not much attempt has been made to understand the relationship between particle attributes and the conditions under which the particles are formed from a thermodynamic viewpoint.

In this article, we propose a framework that offers a thermodynamic perspective in selecting particle-formation process parameters such as temperature, pressure, solvent used, feed concentration, and CO2-to-feed ratio such that the desired product particle attributes can be achieved. Solubility data are represented on a phase diagram so that regions of composition, temperature, and pressure in which a solid product would be obtained can be conveniently identified. Subsequently, operating conditions that effectively control particle attributes such as average particle size and size distribution, product yield, and ease of operation can be properly selected. Salicylic acid is chosen as an example for this study because of the readily available solubility data in supercritical CO2. Ethanol and acetone are used as cosolvents in this system since the solubility of drugs in supercritical CO2 was reported to be enhanced by the addition of a cosolvent, such as an alcohol.10 Various studies have shown that the resulting antisolvent effect would impose a significant effect on drug particle size.11 The solubility effect of salicylic acid with the use of cosolvents on the particle

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Figure 3. Schematic diagram and photo of the spray nozzle.

formation process and comparing the final average particle size and size distribution are the main focuses in this study. Experimental Section Materials. The carbon dioxide used in the solubility study was supplied by Hong Kong Specialty Gases with a purity of 99.99%. Salicylic acid (SA) with a minimum purity of 99.5% was obtained from Riedel-deHae¨n. Ethanol was obtained from Merck with a purity not less than 99.9%. Acetone with a minimum purity of 99.5% was obtained from Scharlau Chemie, S.A. Acetate buffer solution required for the dissolution experiment was made up of sodium acetate trihydrate from Riedel-deHae¨n (99.5%) and glacial acetic acid from Fisher Chemicals (99.83%). Materials required for scanning electron microscope (SEM) sample preparation are 12 mm aluminum specimen mount stubs used for sample mounting purposes and double-sided carbon 12 mm adhesive tabs for sample attachment. All chemicals were used directly as received. Apparatus and Procedure. A phase equilibrium analyzer (PEA) unit, manufactured by Thar Design Technologies (PEA30ML), was used to determine the solubility of SA with different modifiers in supercritical CO2. It consists of a syringe pump (240 mL), a volume-variable view cell (25 mL), the PEA vessel housing a magnetic stirrer to agitate the contents, and an external temperature-controlling water/ethylene glycol mixture circulating bath to maintain a preset temperature. A schematic diagram of the PEA apparatus is shown in Figure 1. This system automatically records parameters such as pressure, temperature, volume, and density. Located on the bottom of the vessel is a sapphire window, which provides visual access via a camera attached to a television monitor. The view window of the variable-volume vessel is used to visually determine the point of solubility and solute precipitation (cloud point) from the appearance and disappearance of the solid initially placed in the vessel.12,13 Different weights of SA (1.5-6 mg) were investigated in this experiment to determine its solubility in CO2. The amount of cosolvent used as modifier in the system was set to 1% (wcosolvent/ wCO2). The syringe pump was filled with CO2 to be compressed, and the pressure was maintained using a computerized autocontrol movable piston while the temperature was preset to 45 °C (accurate to (0.2 °C). Temperature was monitored by a type-K thermocouple, and pressure was measured by a Honeywell pressure transducer (accurate to (0.1%). These condi-

Table 1. Solubility Results of Salicylic Acid in CO2 (Vessel Conditions) run E1 E2 E3 E4 E5 E6 E7 E8 E9 E10 E11 E12 E13 E14 E15 E16 E17 E18 E19 E20 E21 E22 E23 E24 E25 E26 E27 E28 E29 E30 E31 E32

modifier none

T (K)

P (bar)

y × 103

F (g/L)

318

110 112 142 146 98.3 99.8 102.2 103.4 104.0 109.2 112.0 107.4 110.7 112.4 115.2 116.6 120.8 123.8 106.9 109.5 116.4 141.0 160.6 198.5 244.3 125.7 126.5 129.8 157.1 182.4 220.7 252.8

0.281 0.353 0.281 0.353 0.128 0.185 0.217 0.246 0.271 0.314 0.363 0.128 0.185 0.217 0.246 0.271 0.314 0.363 0.156 0.202 0.237 0.265 0.299 0.343 0.369 0.156 0.202 0.237 0.265 0.299 0.343 0.369

591 602 622 639 454 479 503 522 536 579 591 384 420 438 460 480 511 526 563 569 610 721 759 812 854 538 543 560 665 712 777 811

328 1% ethanol

318

328

1% acetone

318

328

tions are preset to supercritical conditions according to the amount of modifier used.14 The PEA vessel is equipped with a computer-controlled movable piston that allowed the system volume (6-25 mL) to be modified during operation. First, the volume in the vessel is adjusted until a clear cloud point (the point where SA drops out of the solution) can be observed. Once this happens, the pressure is increased again to the point where all solids disappear. The final pressure at this condition is recorded. With a known amount of CO2 transferred from the syringe pump to the PEA vessel via a valve, the solubility at this particular temperature and pressure can be calculated. When data has been collected for 45 °C, the system temperature is increased to 55 °C and the points of precipitation and solid disappearance are observed by changing the pressure of the system. In this way, two data points with the same solubility


Figure 4. 3D phase diagram of SA + EtOH + CO2 at 45 °C.

but at different temperature and pressure are obtained. Each solubility point is determined twice to ensure reproducibility. After each run, the system is vented, cleaned with ethanol, and dried prior to the next experiment. In the PCA process, supercritical fluid is used as an antisolvent that causes precipitation of the SA dissolved initially in a liquid solvent. Supercritical CO2 is first pumped into the top of the high-pressure vessel by a high-pressure pump. Once the system reaches steady state, the SA-dissolved liquid solution is then introduced into the vessel at an even higher pressure (typically +20 bar) through a coaxial nozzle, so as to form fine droplets in the compressed CO2. The antisolvent effect is brought about by the dissolution of the supercritical fluid into the liquid droplets via a large volume expansion, leading to a reduction in the liquid solvent power. This causes a sharp rise in the supersaturation within the liquid mixture and the resulting formation of small and uniform particles. These fine particles are collected on a filter at the bottom of the vessel while the fluid mixture (supercritical fluid + solvent) then exits the vessel and flows to a cyclone where the conditions (temperature and pressure) allow for gas-liquid separation. After a sufficient amount of particles are formed, liquid solution pumping is stopped and pure supercritical fluid continues to flow through the vessel to remove residual solvent before particle collection takes place. The PCA equipment (schematic diagram shown in Figure 2) including the vessels and piping was supplied by Thar Design Technologies, Inc. The CO2 supply is connected to a cooler that keeps the CO2 in the liquid phase to be pumped to the heater at experimental operating conditions. A flow meter is also installed to constantly monitor the flow rate of CO2 through the system. The high-performance solution pump is set

Figure 5. (a) Vertical cut of prism along SA-CO2 surface at 45 °C and (b) vertical cut of SA in CO2 with 1% ethanol used as modifier in Figure 4 at 45 °C.

to deliver 0.01-0.5 mL/min into the precipitation vessel. Both the solution and CO2 flow through a spray nozzle into the precipitation vessel with a vessel volume of 100 mL. The pressure of the vessel is controlled by a back-pressure regulator (BPR) after a metal filter located at the bottom of the vessel of pore size 5 µm for particle collection. The remaining fluids are sent to the cyclone separator, where the remaining solvents are recollected while the vapor is then vented out of the system. Temperature control is monitored by a computerized system governing the whole PCA system, including the outer and inner vessel temperatures. It is important to note that the nozzle used in this PCA process is assembled together by merely tube fittings into a coaxial flow nozzle. A 1/16 in. tube with an outlet of 0.1 mm is used as the nozzle inner tube for solution flow. This tube was placed into a tube fitting of 1/8 in. female run tee fit for the flow of supercritical CO2 to enter the vessel. This tube arrangement was used to enhance the mixing effect of the two fluids to produce smaller solution droplets. A photo and a schematic diagram of the nozzle can be viewed in Figure 3. The solubility results from the PEA experiment were used as the initial concentrations of the solution and operating conditions for the PCA process. The system is also rinsed through at the end of each run at a condition selected in the fluid phase before the next experiment is commenced to remove SA that has remained in the pipelines. Analysis. A high-resolution scanning electron microscope (SEM) JSM-6700F model supplied from Jeol was used for particle size characterization because of its ability to view smaller particles at high resolution up to 10 nm. This model employs a field-emission gun for the electron source and computer technology for the image-display system. A gold

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Figure 6. Isobaric cuts showing data from Ke et al.18 at 45 °C.

Figure 7. (a) Vertical cut of triangular prism along SA-CO2 surface at 55 °C and (b) vertical cut of SA in CO2 with 1% ethanol used as modifier at 55 °C.

sputter coater, supplied by Emitech (K575X Turbo sputter coater) is used in sample preparation to allow the sample to be conductive for viewing. For particles that can be counted, the longest length of each particle was measured as the characteristic length to produce a particle size distribution (PSD). For each sample, 300 particles were measured and counted by image analysis. The count from these measured particles was used to calculate the average particle size and PSD for each operated condition. To study the effect of the reduced particle size obtained in this study, a dissolution rate experiment is carried out as a comparison with particles that have not been processed by PCA.

Figure 8. 3D phase diagram of SA + Ace + CO2 at 45 °C.

For the dissolution rate system (Distek 2100C), a USP standard test method is used with 500 mL of acetate buffer in each tank at a set temperature of 37 °C. Paddle stirrers are chosen, and the stirring speed is set at 50 rpm. The experiment was carried out in all eight tanks of the equipment to ensure reproducibility. For each run, 80 mg of the SA particles were placed in empty teabag sachets for dissolution into acetate buffer (pH 4.5). The dissolution experiment was carried out for 120 min with sampling intervals from 3 to 10 min. For each sample, a 4-time dilution was required before it could be analyzed in the UVvis spectrometer.

Ind. Eng. Chem. Res., Vol. 46, No. 11, 2007 3585 Table 2. Summary of the PCA Experimental Conditions sample preparation run

cosolvent

C1 C2 C3 C4 C5 C6 C7 C8

ethanol

operating condition

operation flowrate

weight of SA (g)

cosolvent used (mL)

pressure (bar)

temp. (°C)

CO2 pump (g/min)

soln. pump (mL/min)

9.333

200

83 92 82 93 96 107 99 114

45 55 45 55 45 55 45 55

28.32

0.50

27.87

0.50

27.90

0.34

27.74

0.34

acetone

12

200

14

200

18

200

Table 3. Summary of Particle Sizes Obtained in PCA Experiments with Ethanol as Cosolvent

run

average particle size (nm)

minimum particle size (nm)

maximum particle size (nm)

C1 C2 C3 C4

91.14 102.75 84.57 82.24

33.33 37.50 30.77 28.57

391.30 300.00 266.67 342.86

Results and Discussion The solubility results obtained from the PEA experimental setup can be reviewed in Table 1 in mole fraction of SA, y ((moles of SA)/(total moles)) in its mixture with CO2 (containing 1% ethanol and acetone as modifiers for runs E5-E32). It can be seen that SA has very low solubility in supercritical CO2. Since CO2 is a nonpolar fluid that exhibits very weak van der Waals forces and a low dielectric constant and lacks a dipole moment, the CO2-CO2 interactions are relatively weak, which is the reason for the poor solvating properties of the gas. Increasing the system pressure is one method of overcoming the effect of CO2-CO2 interactions. The free volume difference between SA and CO2 is decreased, potentially resulting in enhanced solubility when pressure is increased. The results also reveal that the solubility of SA in supercritical CO2 has increased significantly with the addition of modifiers by observing the lower pressure required for SA solubility. Physical forces such as hydrogen bonding play an important role in the solute-solvent interactions that characterize the phase behavior. A solution will occur when the intermolecular attractive forces of solute and solvent are similar. CO2 exhibits far weaker van der Waals forces than traditional organic solvents; thus, additives that can achieve the same limited intermolecular forces (ethanol and SA in this case) will easily solubilize in CO2. SA possesses a hydroxyl group that easily interacts with the hydroxyl group of the ethanol to improve its solubility in supercritical CO2. Acetone, however, does not modify SA solubility as well as ethanol. This is due to the less attractive intermolecular forces between the SA and the acetone that lowered the solubility in CO2. Hence, a higher pressure is required to force the SA to dissolve in the acetone-supercritical CO2 mixture. The solubility data obtained here are only a small part of the overall solid-fluid equilibrium phase behavior of the SACO2-modifier system, which can be represented using relevant phase diagrams.15 Figure 4 shows an isothermal phase diagram of the ternary system SA-CO2-ethanol at 45 °C. The vertical axis signifies the pressure, while the base of the triangular prism is a composition triangle, with each vertex corresponding to a pure component. The diagram features a solubility surface between the fluid phase and the solid SA, which effectively divides the composition space into two regions: an unsaturated fluid region (near the CO2-ethanol edge) and a two-phase region where solid SA would crystallize out (near the SA

Table 4. Summary of Particle Sizes Obtained in PCA Experiments with Acetone as Cosolvent

run

average particle size (nm)

minimum particle size (nm)

maximum particle size (nm)

C5 C6 C7 C8

63.35 91.99 116.45 81.55

23.53 30.77 50.00 33.33

148.15 507.69 483.33 215.38

vertex). Note that the diagram is not drawn to scale for a clearer view of the solubility surface near the CO2 vertex. All solubility data points taken at this temperature should lie on this solubility surface. For easier visualization, various cuts (2D plots) can be taken to reduce the dimensionality of the ternary phase diagram. First consider a vertical cut along the SA-CO2 face of the triangular prism, the corresponding plane of which passes through the SA edge and the line representing a mixture of 1% ethanol in CO2. An enlarged portion of this cut is shown in Figure 5a. The triangles shown here represent experimental solubility data of SA in pure CO2 at 45 °C obtained with the PEA equipment (runs E1 and E2). Literature data from Bristow et al.16 (filled circles) and Gurdial and Foster17 (open circles) are plotted alongside for comparison. It can be seen that, in general, the experimental data are in fair agreement with the literature data. Another vertical cut at constant ethanol-to-CO2 ratio is shown in Figure 5b, featuring experimental solubility data of SA in CO2 with 1% ethanol at 45 °C (runs E5-E11). Unfortunately, no literature data lying on the same cut is available for comparison. Second, horizontal cuts can be taken along the pressure axis of the isothermal triangular prism. Such isobaric cuts are suitable for plotting solubility data at constant pressure, as shown in Figure 6. Isobaric cuts at five different pressures (superimposed on the same coordinates as different colors) are shown based on the data obtained by Ke et al.18 The phase behavior at 55 °C can be represented using a similar triangular prism diagram (not shown), except that the location of the solubility surface would be different. The vertical cut along the SA-CO2 surface is shown in Figure 7a, featuring experimental data obtained at 55 °C (runs E3 and E4) as well as literature data at the same temperature. It is evident from the figure that agreement with literature data is reasonably good. Data with 1% ethanol as modifier in the system are shown on the corresponding cut in Figure 7b (runs E12-E18). The isothermal phase diagram of the SA-CO2-acetone system at 45 °C also takes the shape of a triangular prism, as shown in Figure 8. The SA-CO2 face is exactly the same as that in Figure 4, but ethanol is replaced by acetone. Two vertical cuts, at 1.1 mol % and 3.5 mol % acetone in CO2, respectively, are shown in the prism. Figure 9a shows an enlarged portion of the cut at 1.1 mol % (1% by weight) acetone in hollow circles, featuring experimental data from runs E19-E25. Only one set of solubility data for this system at these two temperatures is

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Figure 9. Vertical cut at 3.5% and 1.1% acetone as modifier at (a) 45 °C and (b) 55 °C of the triangular prism.

available in the literature (e.g., ySA ) 0.000 68 at 86 bar),19 and it is for 3.5 mol % acetone shown in filled circles (in other words, data presented by Gurdial et al. lies on the other vertical cut, 3.5%, shown in Figure 8). Figure 9b shows the vertical cut at 1.1 mol % acetone of the isothermal phase diagram of the SA-CO2-acetone system at 55 °C, featuring experimental data from runs E26-E32. The three-dimensional phase diagram for 55 °C is not shown here because it is similar to the one shown in Figure 8. PCA A summary of operating conditions, sample composition, and flow rates of CO2 and solution for the PCA experiments can be viewed in Table 2. A total of eight runs using two different solvents are conducted to examine the effects of solvents used as well as the effects of different operating conditions on particle attributes. The operating conditions are selected with the aid of the phase diagram to ensure that solids precipitate out from the single fluid phase. A 10 bar reduction in pressure from the solubility data was used as the target precipitation condition in the PCA experiments, so as to guarantee that the operating point is located in a solid-fluid region. However, the difficulty in maintaining constant flow rate CO2 and solvent from the pumps as well as the kinetics of particle formation contributes to an actual condition that may deviate from the target. Salicylic acid is commonly used in the process without the aid of a solvent.10 To provide comparison with the supercritical processed particles, unprocessed particles were analyzed as received using SEM. As can be seen in Figure 10, the original unprocessed particles are of a wide range of sizes and shapes. Together in the sample exist fibers, big flakes, threads, and round- and rod-shaped particles. The morphology of the particles is not uniform or controlled. When particles can be counted,

the average particle size of the original SA was found to be approximately 30-50 µm. The particles provided by RiedeldeHae¨n can be said to be random in particle size and difficult to characterize. In contrast, the average particle size obtained in the PCA experiments under all conditions is approximately 100 nm (0.1 µm). The average particle size of each of the conditions is given in Tables 3 and 4 for ethanol and acetone as cosolvent, respectively. The run numbers correspond to Table 2 of individual experimental conditions used in this study. As a comparison, most of the reported average particle sizes using the PCA process are in the range of 0.2-500 µm. Figure 11 shows the SEM images of the particles that were formed in run C1 (using ethanol as solvent) under magnification of 30 000 and 55 000 times. Many rod-shaped particles are observed, and agglomeration is apparent. As can be seen, occasionally large particles of approximately 1 µm can be observed among the particles collected. A summary of the PSD obtained from processed SA using ethanol as the solvent is represented in Figure 12, with result details presented in Table 3. Precipitating conditions for runs C1-C4 are shown on the phase diagram in Figure 13, along with the corresponding solubility curves at different temperatures obtained from the PEA experiments. Comparing the conditions in Figure 13 (particularly the distance between the operating point and the solubility surface, which represents the degree of supersaturation) with the corresponding particle results, it can be observed that smaller and more uniform particles can be collected at conditions operated at higher supersaturation. For example, it can be observed that particles produced at conditions C3 and C4 have sharp and quite normal distribution with smaller average particle sizes, 84.57 and 82.24 nm, respectively. These results correspond neatly to the expected trends of the particle formation for the PCA process, as some authors suggested that rapid precipitation causes the solute to behave as discrete units and precipitate out as micro-/nanoparticles.20,21 Runs C3 and C4 are conditions with relatively high supersaturation (almost 30 bar). Experiments that were operated at lower supersaturation (runs C1 and C2), which is closer to the solubility curve, resulted in an irregular (multimodal) PSD and slightly larger particles. Precipitation of SA with acetone used as a solvent resulted in more uniform, defined particles. As an example, SEM images with magnification of 30 000 and 80 000 times of particles from run C5 can be viewed in Figure 14. Although most particles here seemed to be agglomerated together, small individual particles can quickly be distinguished in this sample. The particles here appeared to be in small rod/spherical shape, but occasionally big particles of approximately 1-2 µm in size can also be seen. A summary of the PSD of particles obtained from runs C5-C8 is shown in Figure 15. The PSD results from runs with acetone as solvent reveal similar trends as those with ethanol. For example, smaller and more uniform PSD is obtained for C8 as compared to C6. As can be seen on the phase diagram in Figure 16, the operating point of run C8 corresponds to a much higher supersaturation than that of run C6 (about 80 bar in pressure for run C8 and 20 bar for run C6). Because of this higher supersaturation, the particles precipitate out of the droplet when it meets the dense CO2 medium to form smaller and more uniform particles. However, the opposite is observed for the conditions of runs C5 and C7, both carried out at 45 °C. The smallest average particle size of 63 nm is obtained for C5, which is located very near to the solubility curve at 116 bar (solubility point E21). At the higher supersaturation conditions in run C7, the


Figure 10. SEM images of the original unprocessed salicylic acid.

Figure 11. SEM image of the PCA processed particle with ethanol as the cosolvent (run C1).

Figure 13. Particle formation conditions (runs C1-C4) with 1% ethanol as modifier. Figure 12. Comparison of PSD of different conditions with ethanol as cosolvent.

average particle sizes obtained were the largest, with a wide and irregular PSD. Despite the previously mentioned statement where smaller particles are found to form at a higher supersaturation region, the high supersaturation condition at C7 may

lead to significant agglomeration, which gives rise to the irregularly peaked PSD. Dissolution Rate The nanoparticles obtained from the PCA experiments are expected to have much enhanced dissolution rates versus that

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Figure 14. SEM image of the PCA processed particle with acetone as the cosolvent (run C5).

Figure 17. Dissolution rate comparison of original SA particles with supercritical fluid processed (SC-Proc) SA particles. Figure 15. Comparison of PSD of different condition with acetone as cosolvent.

particles (∼60 nm) enhanced the dissolution rate by almost three times that of the original (∼30 µm) SA particles. This is a size reduction of 500 times, which significantly speeds up the dissolution rate of the unprocessed drug particles. At 55 min, more than 90% of the supercritical fluid processed (SC-Proc) SA has been dissolved in the buffer solution, while the original SA particles are only about 45% through the dissolution. At the end of the 2 h experiment, more than 20% of the original SA particles still remain undissolved. Conclusion

Figure 16. Particle formation conditions with 1% acetone as modifier.

of the original particles, since smaller particles would experience faster dissolution due to better transport properties and larger surface-to-volume ratio. This reduction in dissolution time would greatly enhance the efficiency of drugs. The improvement of the dissolution profile of the nanoparticles produced by PCA using supercritical CO2 can be shown in Figure 17. The smaller

Supercritical carbon dioxide offers several attractive technological scenarios for pharmaceutical processing that could result in significantly reduced usage of conventional liquid solvents and the production of relatively contaminant-free products. The use of supercritical CO2 for nanoparticle formation has been shown to have a significant impact on the high-value specialty materials industry, such as pharmaceuticals, cosmetics, and superconductors. In particular, with the use of nanoparticles in a drug, dosage forms can be decreased and side effects of the drug can also be minimized because of the increased dissolution rate. This study on the PCA particle formation process conveniently demonstrated a thermodynamic-based framework in producing nanoparticles by first identifying regions on the phase


diagram of the supercritical CO2 + cosolvent + solute system in which the desired product can or cannot be obtained. Solubility data are put in perspective by plotting them on relevant cuts of the phase diagram, so as to give most of the required information for choosing parameters of the PCA process. Operation inside the right region with an appropriate level of supersaturation would ensure successful production of high-quality (smaller and more uniform) particles in the nanorange. Although this study has shown that supersaturation has a significant effect on final particle quality, more research is required to fully understand the effect of different types and amounts of solvents on the average particle size and the size distribution of a drug in supercritical fluid processes. A suggested future study would be to locate the metastable zone for each of the systems and develop a crystallization strategy in controlling the particle size as well as producing particles with a narrow PSD. However, comprehension of the fluid dynamics, the nucleation phenomenon, the crystal growth under these specific conditions, and the particle agglomeration in the jet are also essential for a thorough understanding of the particle formation process in PCA. Literature Cited (1) Rabinow, B. E. Nanosuspensions in drug delivery. Nat. ReV. Drug DiscoVery 2005, 3, 785-796. (2) Liveridge, G. G.; Cundy, K. C. Particle size reduction for improvement of oral bioavailability of hydrophobic drugs. I. Absolute oral bioavailability of nanocrystalline danazol in beagle dogs. Int. J. Pharm. 1995, 125, 91-97. (3) Moghimi, S. M.; Hunter, A. C.; Murray, J. C. Nanomedicine: Current status and future prospects. FASEB J. 2005, 19, 311-330. (4) Langer, R. New methods of drug delivery. Science 1990, 249, 15271533. (5) Diederich, J. E.; Muller, R. H. Future strategies for drug deliVery with particulate systems; MedPharm Scientific Publishers: Berlin, 1998. (6) Pace, S. N.; Pace, G. W.; Parikh, I.; Mishra, A. K. Novel injectable formulations of insoluble drugs. Pharm. Technol. 1999, 23, 116-134. (7) Benedetti, L.; Bertucco, A.; Pallado, P. Production of micronic particles of biocompatible polymer using supercritical carbon dioxide. Biotechnol. Bioeng. 1997, 53, 232-237. (8) Chavez, F.; Debenedetti, P. G. Estimation of characteristic time scales in the supercritical antisolvent process. Ind. Eng. Chem. Res. 2003, 42, 3156-3162.

(9) Jarmer, D. J.; Lengsfeld, C. S.; Randolph, T. W. Manipulation of particle size distribution of poly(L-lactic acid) nanoparticles with a jetswirl nozzle during precipitation with a compressed antisolvent. J. Supercrit. Fluids 2003, 27, 317-336. (10) Subramaniam, B.; Rajewski, R. A.; Snavely, K. Pharmaceutical processing with supercritical carbon dioxide. J. Pharm. Sci. 1997, 86, 885890. (11) Chattopadhyay, P.; Gupta, R. B. Production of antibiotic nanoparticles using supercritical CO2 as antisolvent with enhanced mass transfer. Ind. Eng. Chem. Res. 2001, 40, 3530-3539. (12) Young, T. J.; Mawson, S.; Johnson, K. P. Rapid expansion from supercritical to aqueous solution to produce submicron suspensions of waterinsoluble drugs. Biotechnol. Prog. 2000, 16, 402-407. (13) Weinstein, R. D.; Muske, K. R.; Moriarty, J.; Schmidt, E. K. The solubility of benzocaine, lidocaine, and procaine in liquid and supercritical carbon dioxide. J. Chem. Eng. Data 2004, 49, 547-552. (14) Day, C. Y.; Chang, C.; Chen, C. Y. Phase equilibrium of ethanol + CO2 and acetone + CO2 at elevated pressures. J. Chem. Eng. Data 1996, 41, 839-843. (15) Harjo, B.; Ng, K. M.; Wibowo, C. Synthesis of supercritical crystallization processes. Ind. Eng. Chem. Res. 2005, 44, 8248-8259. (16) Bristow, S.; Shekunov, B. Y.; York, P. Solubility analysis of drug compounds in supercritical carbon dioxide using static and dynamic extraction systems. Ind. Eng. Chem. Res. 2001, 40, 1732-1739. (17) Gurdial, G. S.; Foster, N. R. Solubility of o-hydroxybenzoic acid in supercritical carbon dioxide. Ind. Eng. Chem. Res. 1991, 30, 75580. (18) Ke, J.; Mao, C.; Zhong, M.; Han, B.; Yan, H. Solubilities of salicylic acid in supercritical carbon dioxide with ethanol cosolvent. J. Supercrit. Fluids 1996, 9, 82-87. (19) Gurdial, G. S.; Macnaughton, S. J.; Tomasko, D. L.; Foster, N. R. Influence of chemical modifiers on the solubility of o- and m-hydroxybenzoic acid in supercritical CO2. Ind. Eng. Chem. Res. 1993, 32, 1488-1497. (20) Chattopadhyay, P.; Gupta, R. B. Supercritical CO2-based production of fullerene nanoparticles. Ind. Eng. Chem. Res. 2000, 39, 2281-2289. (21) Reverchon, E. Supercritical-assisted atomization to produce microand/or nanoparticles of controlled size and distribution. Ind. Eng. Chem. Res. 2002, 41, 2405-4211.

ReceiVed for reView August 24, 2006 ReVised manuscript receiVed February 24, 2007 Accepted March 23, 2007 IE0611204

Producing Nanoparticles Using Precipitation with Compressed

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