Article pubs.acs.org/IECR
Recrystallization of Adefovir Dipivoxil Particles Using the Aerosol Solvent Extraction System Process Joon-Hyuk Yim,† Woo-Sik Kim,‡ and Jong Sung Lim†,* †
Department of Chemical and Biomolecular Engineering, Sogang University, Seoul 121-742, Korea Department of Chemical Engineering, ILRI, Kyunghee University, Kyungki-do 446-701, Korea
‡
ABSTRACT: In this study, the adefovir dipivoxil particles were recrystallized by using the aerosol solvent extraction system (ASES) process. Supercritical carbon dioxide, which is known to be a green solvent, was adopted as an anti-solvent. The effects of process parameters such as temperature, pressure, solution concentration, and solution injection rate on particle size and its distribution were investigated. To explore the influence of solvents on particle production, ethanol (C2H5OH), methanol (CH3OH), and IPA (isopropyl alcohol, C3H8O) were used as a dissolving solvent for adefovir dipivoxil. As a result, particle size decreased when the system temperature decreased and the system pressure increased. Higher concentration of adefovir dipivoxil in the solution and increasing the solution injection rate also increased particle size. When we use three different kinds of solvents, the order of recrystallized particle size and the width of particle size distribution was methanol < ethanol < IPA. A scanning electron microscope was used to observe the morphology and size of the adefovir dipivoxil particles recrystallized by the ASES process. The mean particle size and its distribution of processed particles were measured by image analysis software.
1. INTRODUCTION
The ASES process is one of the more well-known methods recognized in this field. ASES is used in the case where a solute produced into fine particles is insoluble within the supercritical fluid. The processed particles are prepared by sudden solubility reduction of the solvent when the solution containing the target materials and appropriate solvent is dissolved in the supercritical solvent. Its effectiveness is in the preparation of submicrometer particles of thermally sensitive medicine or proteins without residual solvent or the need for a washing and drying process. Also, it is generally known for minimizing process parameters for each batch operation. Due to these advantages, the ASES process has been utilized by many research groups in various areas such as polymers, catalyst precursors, coloring matters, superconductors, explosives, pharmaceutical compounds, and biopolymers.7 The ASES process involves a spray solution containing the material of concern directed into the precipitator where a continuous flow of supercritical fluid is established. Fine liquid droplets are obtained by spraying the solution into the precipitator which is filled with supercritical anti-solvent. A filter collects the droplets as fine particles at the bottom of the precipitator after going through a two-way mass transfer with the supercritical anti-solvent. As a result, the particles produced by this process typically have a very small size and narrow particle distribution.8 Meanwhile, adefovir dipivoxil (9-[2-bis(pivaloyloxymethyl)phosphonmethoxyethyl]adenine) has been spotlighted in the pharmaceutical industry for effectively treating infections of the hepatitis B virus (HBV). A trademarked name of adefovir dipivoxil, is Hepsera, which is an orally bioavailable prodrug of
In the pharmaceutical industry, micronization techniques are used to improve the bioavailability of drugs within biological environments. The bioavailability of a drug is improved by decreasing the particle size or maximizing the particle surface area through a reduction in the particle size. Pharmaceuticals with a small and narrow particle size distribution play a vital role in the design of a wide range of drug delivery systems (DDSs).1,2 To reduce particle size with the aim of increasing bioavailability, there are many conventional methods that have been used such as milling, spray-drying, freeze-drying, and recrystallization of the solute particles from solutions using liquid anti-solvents. However, there are numerous disadvantages such as poor size control, unsuitable morphology, thermal and chemical degradation of products, the use of large amounts of solvent and associated disposal problems, wide particle size distributions, and solvent residues.2−4 To overcome these drawbacks of conventional methods, many researchers have utilized supercritical fluids. Supercritical fluids (SCF) are used in many industrial processes and have a potentially wide range of new applications. One of the important advantages of SCF includes a mild operating temperature. Therefore, this technique could be used for materials that are sensitive to temperature, reduction of particle size to submicrometer levels, and narrow particle size distribution. Among the selection of SCF, supercritical CO2 is widely used in both the process for designing particles of organic and pharmaceutical compounds due to its environmentally benign nature and low cost.5,6 There are well-known particle formation methods by means of SCF technology such as rapid expansion of supercritical solution (RESS) and supercritical anti-solvent (SAS). The SAS process is classified into gas anti-solvent (GAS), aerosol solvent extraction system (ASES), particles from gas saturated solutions (PGSS), and solution enhanced dispersion by supercritical fluid (SEDS).6 Among these methods, we used the ASES process in this study. © 2014 American Chemical Society
Received: Revised: Accepted: Published: 1663
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Figure 1. (a) Chemical structure and physical property of adefovir dipivoxil. (b) SEM image of adefovir dipivoxil (form-I) (×1000).
Figure 2. Schematic diagram of the experimental apparatus: (1) CO2 cylinder; (2) cooling circulator; (3) high pressure pump; (4) vessel; (5) pressure transducer; (6) thermocouple; (7) rupture; (8) air bath; (9) filter; (10) back-pressure regulator; (11) separator; (12) rotameter; (13) solution pump; (14) solution tank; (15) temperature controller; (16) pressure indicator; (17) temperature indicator; (18) heat exchanger.
9-[2-(phosphonylmethoxy)ethyl]adenine (adefovir).9 Its chemical structure and scanning electron microscopy (SEM) image are shown in Figure 1. Adefovir dipivoxil is also effective against the human immunodeficiency virus (HIV), the Epstein−Barr virus, retroviruses, herpesviruses, cytomegaloviruses, and other DNA viruses.10 On the other hand, well-known hepatitis B virus treatments such as Interferon alfa-2b and Lamivudine are known to have negative side effects involving depression and HBV resistance, respectively.10,11 Therefore, adefovir dipivoxil is mainly used to treat HBV due to a lack of adverse effects without HBV resistance. The purpose of this study is to explore the micronization of adefovir dipivoxil particles with the aim of improving pharmaceutical bioavailability. The crystallization of adefovir dipivoxil was studied by some other research groups. However, this study is the first trial of recrystallization of adefovir dipivoxil using supercritical fluid by the ASES process.
Particularly, this study is focused on effective particle size control by changing process parameters such as temperature, pressure, and concentration for improving pharmaceutical bioavailability in the pharmaceutical field. In our previous study, we did the RESS experiment on adefovir dipivoxil particles.12 However, the RESS process has some minor problems, such as wide particle distribution and random shape of particle. So, we tried to recrystallize adefovir dipivoxil particles using the ASES process to overcome these drawbacks in this work. By using the ASES process, we have produced submicrometer particles of adefovir dipivoxil for the application in a DDS based on microparticles formulated with polymers. The effects of the general process parameters were studied with consideration of temperature, pressure, concentration, solution injection rate, and solvent influence on particle size and the morphology of adefovir dipivoxil. 1664
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Figure 3. Measured solubility of adefovir dipivoxil in supercritical CO2 (mole fraction vs pressure). Temperatures: (●, black) 308.15, (▼, red) 313.15, (■, green) 318.15, (◆, yellow), 323.15, (▲, blue), 328.15, and (⬢, purple) 333.15 K. Reproduced with permission from ref 12. Copyright 2013 Elsevier.
Figure 5. Adefovir dipivoxil particle size distribution with increasing temperature (the effect of temperature on adefovir dipivoxil particles at 10 MPa, 1.0 wt % concentration, ethanol solvent, 0.2 mL/min solution injection rate, and 0.53 kg/h CO2 feed). Symbols are temperatures: (□, black) 308.15, (○, red) 313.15, (△, blue) 318.15, and (▽, green) 323.15 K.
2. EXPERIMENTAL SECTION 2.1. Materials. The adefovir dipivoxil (purity higher than 99.9%) was supplied by a Korean pharmaceutical company (Daehee Chemical Co., Gyeonggi-do, Korea). The chemical structure and physical properties of adefovir dipivoxil as well as a SEM image of the original adefovir dipivoxil are given in
Figure 1. Carbon dioxide (purity 99%) used as an anti-solvent for adefovir dipivoxil was obtained from Deokyang Gas Co. (Ulsan, Korea). Isopropyl alcohol (99.9%, Burdick & Jackson Chemicals, USA), ethanol (99.5%, Samchun Chemical Co. Ltd., Seoul, Korea) and methanol (99.5%, Samchun) were used as a
Figure 4. Effect of temperature on adefovir dipivoxil particles at 10 MPa, 1.0 wt % concentration, ethanol solvent, 0.2 mL/min solution injection rate, and 0.53 kg/h CO2 feed (×5000 SEM image). 1665
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Table 1. ASES Experimental Conditions to Obtain Fine Adefovir Dipivoxil Particles solvent name ethanol
syst condition supercritical
ethanol
near-critical
methanol IPA
supercritical supercritical
concn (wt %)
injection rate of solution (mL/min)
feed rate of CO2 (l/min)
10
1.0
0.2
5.0 (0.53 kg/h)
1.0
0.2
5.0
308.15
8 15 20 10
0.2
5.0
308.15
10
0.5 2.0 1.0
5.0
301.15 303.15 303.15 313.15 308.15 308.15
7 7.3 8 7 10 10
1.0
0.5 1.0 0.2
5.0
1.0 1.0
0.2 0.2
5.0 5.0
temp (K) 308.15 313.15 318.15 323.15 308.15
press (MPa)
mean particle size (μm) 0.91 1.08 1.28 1.57 1.55 0.87 0.75 0.73 1.09 1.20 1.34 2.26 2.05 1.88 no particle 0.63 1.57
Figure 6. Effect of pressure on adefovir dipivoxil particles at 308.15 K, 1.0 wt % concentration, ethanol solvent, 0.2 mL/min solution injection rate, and 0.53 kg/h CO2 feed (×5000 SEM image).
solvent for adefovir dipivoxil. All reagents were used without further purification. 2.2. Experimental Apparatus. A schematic diagram of the ASES apparatus used is shown in Figure 2. It was composed of an anti-solvent supplying system, a solution feeding system, a precipitation vessel (KISTEC), two filters (0.5 μm, Swagelok), a back-pressure regulator (Tescom Corp.), and a gas vent
system. A precipitator was placed on the center of the thermostat air chamber. The chamber pressure was controlled by a back-pressure regulator (Tescom) located between the filters and separator (SUS 316). Pure CO2 was cooled by a refrigeration bath circulator (Jeio Tech) and continuously fed into a precipitator from the top of the vessel by using a high pressure pump (Oriental Motors). The system was continuously 1666
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Figure 7. Effect of solution injection rate on adefovir dipivoxil particles at 308.15 K, 10 MPa, 1.0 wt % concentration, ethanol solvent, and 0.53 kg/h CO2 feed (×5000 SEM image).
2.4. Particle Characterization. The morphology of collected particles was analyzed by SEM (JSM-6010LA, Jeol). The samples for SEM were attached by using double-coated adhesive tape and coated with gold by a sputter coater (sputter coater 108auto, Cressington). The particle size distribution (PSD) and average particle size were determined by measuring and counting at least 150 particles which were arbitrarily selected from the SEM images by image analysis software.
vented through passing a back-pressure regulator and dry gas meter (Taekwang Energy S/T-3). The solution containing adefovir dipivoxil was sprayed into the precipitator using a high pressure liquid pump (Oriental Motors) through a fine nozzle (0.63 mm internal diameter) located on the top of the essel. The spray distance from the nozzle to the bottom of the precipitator was fixed at 16 cm in every experiment. The solvent remained on a separator or was vented with CO2 passing through a dry gas meter. 2.3. Experimental Procedure. The precipitation vessel was filled with CO2 until the desired pressure was reached and heated to the desired operating temperature. After the flow rate of CO2 was maintained constantly at a designated value, liquid solution containing adefovir dipivoxil was injected into a precipitator, and the solution was broken up into droplets by a fine nozzle. As the droplets passed through the precipitator charged with CO2, they went through supersaturation by expansion of solvent into supercritical CO2. At this time, the solution became cloudy and followed nucleation. Consequently, they were crystallized into fine particles and collected on a metal filter by a continuous flow of CO2. This process continued until the liquid solution in the solution feed tank was completely injected into the precipitator. At the same time, CO2 continued to pump into the precipitator in order to remove the residual liquid content on the particles and to ensure the remaining particles in the vessel were moved toward the filter. To obtain the collected particles, the valve between the vessel and filter was closed and then the filter was gradually depressurized by using a back-pressure regulator.
3. RESULTS AND DISCUSSION A key point in the ASES process is to thoroughly spray a solution with anti-solvent with a fine nozzle. Fine droplets are then generated in the precipitator as a result. This process is called atomization, expressed by the dimensionless Weber number defined in the ratio of de-formation force and reformation force. Nwe =
ρA v 2d σ
(1)
where ρA is the density of the anti-solvent, v is the relative velocity, and d is the diameter of droplets by spraying solution, which depends on the relative anti-solvent drop velocity and anti-solvent density. The variable σ is the surface tension.13 The numerator of eq 1 refers to the de-formation force, while the denominator refers to the re-formation force. Generally, smaller droplets are formed with higher values of Nwe as a result of atomization. The droplets pass through the evaporation process (mass transfer). The energy for solvent evaporation from the 1667
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Figure 8. Effect of concentration on adefovir dipivoxil particles at 308.15 K, 10 MPa, ethanol solvent, 0.2 mL/min solution injection rate, and 0.53 kg/h CO2 feed (×5000 SEM image).
droplet surface was supplied using the surrounding anti-solvent by conduction and convection. The evaporated solvent is incorporated into the flow of anti-solvent by convection and back-diffusion. The overall rate of evaporation is affected by pressure, temperature, droplets diameter, and the velocity difference between droplets and the surrounding gas.14 Their effect on adefovir dipivoxil particles was investigated in this study. Experimental conditions and results are stated in Table 1. 3.1. Solubility Measurement. The solubility of adefovir dipivoxil in carbon dioxide was measured within the temperature range of 308.15−333.15 K in 5 K intervals in our previous study.12 The experimental result is given in Figure 3. The cloud point pressure was shown to increase linearly with increasing temperatures at a fixed mole fraction of adefovir dipivoxil. The solubility increased in relation to rising pressure and decreased with increasing temperatures for all of the mole fraction range. The solubility also decreased with increasing adefovir dipivoxil concentration in CO2 for all temperature ranges. In the ASES process, the supercritical CO2 was used as an anti-solvent. Therefore, we set the temperature (308.15− 323.15 K) and pressure (7−20 MPa) ranges based on the solubility data as the supercritical CO2 almost cannot dissolve adefovir dipivoxil. 3.2. Effect of Temperature on Particles. The SEM images of Figure 4 show the effect of temperature on particle size and morphology. The temperature of the system ranged from 308.15 to 323.15 K with 5 K increments. A 0.53 kg amount of fresh CO2 was fed into the precipitator per hour by
Figure 9. Adefovir dipivoxil particle size distribution with increasing concentration (the effect of concentration on adefovir dipivoxil particles at 308.15 K, 10 MPa, Ethanol solvent, 0.2 mL/min solution injection rate, and 0.53 kg/h CO2 feed). Symbols are concentrations: (□, black) 0.5, (○, red) 1.0, and (△, blue) 2.0 wt %.
using a high pressure pump. The morphology of particles was not heavily affected. The mean particle size increased from 0.91 to 1.57 μm with increasing temperature. Relatively small droplets were produced by decreasing the temperature due to high gas density, which increases aerodynamic forces and the 1668
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Figure 10. Effect of various solvents on adefovir dipivoxil particles at 308.15 K, 10 MPa, 0.2 mL/min solution injection rate, and 0.53 kg/h CO2 feed (×5000 SEM image).
increasing the injection rate of the solution from 0.2 to 1.0 mL/min. The particle size distribution grew larger by increasing the solution injection rate from 0.2 to 1.0 mL/min. At 0.2 mL/min, the particle size distribution was measured to be the narrowest. Conversely, the largest particle size distribution was observed at 1.0 mL/min. When the injection rate was increased, droplets could not achieve enough mass transfer to reach the fine particles. In addition, due to insufficient CO2, drying droplets of surrounding CO2 collided with another one in the precipitator or melted already recrystallized particles. Insufficient CO2 also reduced the solvent power of CO2 to the solvent. Therefore, large particles which have a large particle size distribution were produced with increasing solution injection rate. 3.5. Influence of Concentration on Particles. In Figure 8, the SEM images show the effect of weight percent of adefovir dipivoxil in ethanol on particle size and morphology. The concentration of adefovir dipivoxil in ethanol varied from 0.5 to 2.0 wt %. As seen in Figure 8, particle size was sensitive to the solute concentration in the liquid. Particle size was shown to increase with increasing adefovir dipivoxil concentration. The smallest particles were prepared by spraying 0.5 wt % adefovir dipivoxil in ethanol solution into CO2 at 308.15 K, 10 MPa, 0.2 mL/min solution injection rate, and 0.53 kg/h CO2 feed rate. As shown in Figure 9, the smallest particle size and the narrowest particle size distribution were observed at 0.5 wt % concentration of adefovir dipivoxil with lowest solute concentration. This result could be explained from the aspect of nucleation and consequent growth of particles. As the
breakup of droplets. Figure 5 shows the measured particle size and distribution. Particle size distribution was also larger with increasing temperature. However, from eq 1, the droplet size increased with decreasing CO2 density by jet breakup and hydrodynamics related to atomization. Both atomization and mass transfer are important in preparing fine particles. Even so, it is difficult to find and explain the tendency of particles since atomization and mass transfer have contrary effects on particles. According to Randolph et al., particle size increases with temperature because mass transfer rather than jet breakup and hydrodynamics controls particle size.15 These results attributed that either atomization or mass transfer predominantly effects particle generation. 3.3. Influence of Pressure on Particles. Figure 6 shows SEM photographs at pressure ranges from 8 to 20 MPa. As shown in Figure 6, adefovir dipivoxil particle size decreased with increasing pressure. The particle size decreased from 1.55 to 0.75 μm with increasing pressure. And, particle size distribution became smaller with increasing pressure. At 8 MPa pressure, the particle size was the largest and its distribution the widest. When the system pressure increased, increased pressure led to smaller particles by enhancing the solvent power of CO2 with regard to the solvent.16 3.4. Influence of Solution Injection Rate on Particles. The injection rate of the solution ranged from 0.2 to 1.0 mL/min (308.15 K, 10 MPa, 1 wt %, and 0.53 kg/h CO2 feed rate). Ethanol was initially used as the primary solvent for adefovir dipivoxil. As shown in Figure 7, the particle size increased by 1669
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Figure 11. Particle formation at near-critical condition on adefovir dipivoxil particles at 1.0 wt % concentration, ethanol solvent, 0.2 mL/min solution injection rate, and 0.53 kg/h CO2 feed (×5000 SEM image).
droplet dried very fast. Therefore, the kind of solvent is one of the important variables for recrystallization. 3.7. Particle Formation in the Near-Critical Region. In this study, we also tried to produce micronized particles in near-critical conditions. We changed the temperature and pressure into a near-critical region, in order to investigate which series of parameters is more effective. The experimental conditions were set at 303.15 K, 8 MPa and 313.15 K, 7 MPa. In Figure 11, the SEM images show the result in near-critical conditions. The processed particles were not observed at 313.15 K, 7 MPa condition. This condition is a gas phase region. So, the solvent power of CO2 is very weak because the CO2 density in the gas region is much lower than its liquid region.19 Therefore, the particles were not produced due to the solvent being insoluble in CO2. On the other hand, the processed particles were observed at 303.15 K, 8 MPa condition. This condition is in the liquid phase region. The solvent power of CO2 is relatively strong because the CO2 density in this liquid region is much higher than its gas region.19 Therefore, the solvent dissolved well in the CO2, and the particles easily precipitated. In addition, we performed the ASES experiment at 303.15 K, 7.3 MPa condition and 301.15 K, 7.0 MPa condition, both within the near-critical liquid region. As shown in Figure 11, particle size increased with decreasing pressure, which demonstrates the same pattern shown in the supercritical condition.
solution became deeper, saturation was reached at an early stage of the process and the growth process superimposed on nucleation.16 In short, larger particles and broader particle size distribution were obtained. 3.6. Influence of Various Solvents. To investigate the influence of solvent on particle formation, ethanol, methanol, and isopropyl alcohol were used as a solvent for adefovir dipivoxil as shown in Figure 10. When using methanol as a solvent, the particle size was measured to be the smallest at 0.63 μm and its distribution the narrowest. However, methanol has a high toxicity factor in the human body. Compared to methanol, ethanol is a good and nontoxic solvent to recrystallize adefovir dipivoxil into submicrometer particles as shown in Figure 10a. When using ethanol as a solvent, the particle size was slightly larger. Meanwhile, the particle size was the biggest and its distribution the widest when isopropyl alcohol was used as solvent, as shown in Figure 10c. This can be explained by the difference of viscosity. Weber reported that increased viscosity leads to increased droplet size.14 The viscosities of methanol, ethanol, and isopropyl alcohol at 298.15 K are 0.5470, 1.0560, and 2.0150 cP, respectively.17 And this also can be explained by the difference of solubility of solvent. Methanol is the most easily dissolved in supercritical CO2 than other solvents.18 So, the smallest particle was obtained because the 1670
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the dissolution rate of poorly water soluble pharmaceuticals. Ind. Eng. Chem. Res. 2000, 39, 4794−4802. (4) Hezave, A. Z.; Esmaeilzadeh, F. Micronization of drug particles via RESS process. J. Supercrit. Fluids 2010, 52, 84−98. (5) Thakur, R.; Gupta, R. B. Rapid Expansion of Supercritical Solution with Solid Cosolvent (RESS−SC) Process: Formation of Griseofulvin Nanoparticles. Ind. Eng. Chem. Res. 2005, 44, 7380−7387. (6) York, P.; Kompella, U.; Shekunov, B. Y. Supercritical Fluid Technology for Drug Product Development; Marcel Dekker: New York, 2004. (7) Yeo, S. D.; Kim, M. S.; Lee, J. C. Recrystallization of sulfathiazole and chlorpropamide using the supercritical fluid antisolvent process. J. Supercrit. Fluids 2003, 25, 143−154. (8) Kim, M. Y.; Lee, Y. W.; Byun, H. S.; Lim, J. S. Recrystallization of Poly(L-lactic acid) into Submicrometer Particles in Supercritical Carbon Dioxide. Ind. Eng. Chem. Res. 2006, 45, 3388−3392. (9) Hou, G.; Yin, Q.; Yang, Y.; Hu, Y.; Zhang, M.; Wang, J. Solubilities of Adefovir Dipivoxil in Different Binary Solvents at 298.15 K. J. Chem. Eng. Data 2008, 53, 1021−1023. (10) Qaqish, R. B.; Mattes, K. A.; Ritchie, D. J. Adefovir dipivoxil: A new antiviral agent for the treatment of hepatitis B virus infection. Clin. Ther. 2003, 25, 3084−3099. (11) Yuen, M. F.; Lai, C. L. Adefovir dipivoxil in chronic hepatitis B infection. Expert Opin. Pharmacother. 2004, 5, 2361−2367. (12) Yim, J. H.; Kim, W. S.; Lim, J. S. Recrystallization of adefovir dipivoxil particles using the rapid expansion of supercritical solutions (RESS) process. J. Supercrit. Fluids 2013, 82, 168−176. (13) Yule, A. J.; Dunkley, J. J. Atomization of Melts; Clarendon Press: Oxford, U.K., 2004. (14) Lefebvre, A. H. Atomization and sprays; Taylor & Francis: London, 1989. (15) 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. (16) Reverchon, E.; Porta, G. D. Production of antibiotic micro- and nano-particles by supercritical antisolvent precipitation. Powder Technol. 1999, 106, 23−29. (17) Viswanath, D. S.; Ghosh, T. K.; Prasad, D. H. L.; Dutt, N. V. K.; Rani, K. Y. Viscosity of liquids; Springer: Berlin, 2007. (18) Lang, Q.; Wai, C. M. Supercritical fluid extraction in herbal and natural product studiesA practical review. Talanta 2001, 53, 771− 782. (19) Gupta, R. B.; Shim, J. J. Solubility in supercritical carbon dioxide; CRC Press: Boca Raton, FL, USA, 2006.
4. CONCLUSION Adefovir dipivoxil particles were successfully recrystallized by using the ASES process. The atomization and mass transfer to produce adefovir dipivoxil particles were easily adjusted by controlling the temperature and pressure of CO2. The operating pressure was relatively lower (7−20 MPa) than the RESS process (20−30 MPa) which was reported in our previous study.12 And, the adefovir dipivoxil particles by the ASES process is smaller (0.63−2.26 μm) than the result of the RESS process (1.54−4.54 μm), and the particle distribution was narrow. In addition, the sphericity and the roundness of processed particles were improved by the ASES process compared with the RESS process. Increasing temperature was shown to increase particle size from 0.91 to 1.57 μm as the predominant effect of atomization by jet breakup and hydrodynamics enhanced the mass transfer occurring between the droplets and the surrounding CO2. Also, increased pressure led to smaller particles by enhancing the solvent power of CO2 to the solvent. Increasing adefovir dipivoxil concentration also led to large particles by obstructing the mass transfer between the droplets and the surrounding CO2 due to the increased viscosity and premature saturation. The faster injection rate resulted in larger particle sizes by lack of mass transfer with the surrounding CO2 and drying time of the droplets, while the higher CO2 velocity resulted in a favorable effect on particles. In addition, ethanol, methanol, and isopropyl alcohol were used as alternative solvents for adefovir dipivoxil. When we used methanol as a solvent, the smallest particle was obtained. Among the three solvents used in this study, ethanol was mainly used since it is a nontoxic and effective solvent to recrystallize adefovir dipivoxil into submicrometer particles. We also tried to produce micronized particle in near-critical conditions. In the gas phase region, particles were not produced because the CO2 density is much lower than in the liquid region. However, particles were easily precipitated in the liquid phase region because of the higher CO2 density of the liquid region. Particle size was also shown to increase with decreasing pressure, representing the same pattern as in the supercritical condition.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by the Human Resources Development program (Grant No. 20114010203090) of the Korea Institute of Energy Technology Evaluation and Planning (KETEP) grant funded by the Korea government Ministry of Trade, Industry and Energy. This work was also supported by a Sogang University Research Grant in 2011.
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REFERENCES
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