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Production of Amoxicillin Microparticles by Supercritical Antisolvent Precipitation Constantinos G. Kalogiannis,† Eleni Pavlidou,‡ and Constantinos G. Panayiotou*,† Departments of Chemical Engineering and Physics, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
Semicontinuous supercritical antisolvent (SAS) precipitation has been employed for the production of micro- and nanoparticles of amoxicillin with controlled size and size distribution. Different mean sizes and size distributions of particles were achieved depending on the parameters of pressure, solution concentration, and organic solvent. The formed particles were spherical, separate, and of size between 0.2 and 1.6 µm. The particles were successfully precipitated from a dimethyl sulfoxide (DMSO) solution and an ethanol/DMSO solution. In our study, high pressures and a coaxial nozzle for the introduction of the organic solution and the SAS were employed, resulting in the increased mixing of the two flows. The precipitated microparticles were analyzed with scanning electron microscopy. X-ray diffraction analysis of amoxicillin microparticles revealed that they become amorphous after SAS treatment. An attempt was made for the explanation of the influence of the different process parameters on the morphology, the mean size, and the size distribution of the precipitated particles. Introduction Many properties of industrial powdered products can be adjusted by changing the particle size and particle size distribution of the powder. This applies in many fields of the industry, from inorganic powders1 to pharmaceuticals.2 Micronization for industrial purposes is mostly carried out by two techniques, recrystallization from solution and comminution. However, these two methods have several drawbacks. Wide size distribution, high thermal and mechanical stress, environmental pollution, large quantities of residual organic solvent, and multistage processes are some of them as Subra et al.3 has pointed out. These drawbacks are the main reasons for the increasing interest in alternative methods of precipitation. Supercritical fluids offer considerable advantages as solvents or antisolvents in crystallization and precipitation processes. This is why their role has been up scaled and their use as solvents and antisolvents is nowadays in the center of attention. In the sensitive area of pharmaceuticals processing, various requirements need to be fulfilled: • Use of the smallest possible amounts of organic solvents • Molecular control of the process • One-stage technique that leads to pure product with no residual solvent • Control of the properties of the formed microparticles • Application on a large field of pharmaceutical compounds Supercritical fluid processes fulfill all these requirements and moreover present numerous other advantages. One of the most important and popular advantages in recent years is the administration of drugs via * To whom correspondence should be addressed. Phone: +302310996223. Fax: +302310996232. E-mail: cpanayio@ eng.auth.gr. † Department of Chemical Engineering. ‡ Department of Physics.
the pulmonary route. Prerequisites for this type of drug administration are the small size of the particles (2 µm), the narrow size distribution, and the absence of organic solvents in the drug. Amoxicillin is a penicillin-like antibiotic used in treatment of certain infections caused by bacteria such as bronchitis, pneumonia, venereal disease (VD), and of ear, lung, nose, urinary tract, and skin infections. It is not, however, easily soluble in water, which leads to overdosing. The precipitation of nanoparticles of amoxicillin results in the increase of the solubility in water allowing for smaller dosages and more rapid and direct usage of the drug. Moreover, the precipitation of the drug as particles of sizes in the region of 2-5 µm allows for the alternative route of pulmonary drug delivery,4-6 increasing, additionally, the efficiency of the drug in case of pulmonary diseases. Reverchon has attempted a supercritical antisolvent (SAS) precipitation of amoxicillin7 from dimethyl sulfoxide (DMSO). However, the precipitation was not 100% successful, yielding coalescing particles or films of amoxicillin. Precipitation of amoxicillin particles was successful using the very toxic and harmful N-methyl pyrrolidone (NMP). The objective of this work is the production of amoxicillin micro- and nanoparticles with well-defined and controllable by the process parameters mean sizes and size distributions, from less harmful organic solvents such as DMSO and EtOH. Experimental Section Apparatus. A schematic diagram of the SAS apparatus that was used in this work is shown in Figure 1. A preliminary description of it was done recently.8 The apparatus consists of two Milton Roy pumps, used for the delivery of the organic solution and the SAS. The precipitation chamber (1) has an internal volume of 50 mL and is equipped with two quartz windows so that the precipitation process may be followed visually. The introduction of the organic solution in the precipitation chamber is done via an orifice
10.1021/ie050654m CCC: $30.25 © 2005 American Chemical Society Published on Web 10/13/2005
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Figure 1. Schematic diagram of the SAS apparatus: (1) precipitation chamber; (2) Milton Roy pump of the organic solution; (3) filters; (4) coaxial nozzle; (5) Tescom back pressure regulator; (6) extraction vessel; (7) dry test flow meter.
Figure 2. Coaxial nozzle employed for the simultaneous introduction of the organic solution and the supercritical antisolvent.
with an internal diameter of 1 mm. The CO2 is introduced via a coaxial nozzle (4) specifically designed for enhancing the mechanical mixing, and ultimately, the intimate mixing of the two flows; this process is termed solution enhanced dispersion by supercritical fluids and has been described by Shekunov, Hanna, and York.9-11 Figure 2 shows the coaxial nozzle. The pressure is controlled by a Tescom back-pressure regulator (5), which is heated in order to avoid condensation and blockage of the flow upon depressurization. Two filters (3) are mounted on the outside of the oven for the collection of the microparticles. In this way, the time-consuming step of dismantling and reassembling the vessel is avoided. Finally, the organic solvent is retained in an extraction vessel (6), while the CO2 is vented through a dry test flow meter (7). Experimental Procedure. At the beginning of each experiment, the precipitation chamber was pressurized with CO2. The temperature was controlled and maintained constant by placing the precipitation cell in an air oven. The CO2 was passed through a coil, allowing it to reach the selected temperature of the oven. The CO2 was passed through a cooler so as to ensure that it was in a liquid state before entering the pump and avoid cavitation. Once the steady-state condition was reached, the organic solution containing the pharmaceutical compound was pumped into the precipitation chamber simultaneously with the supercritical CO2, via the coaxial nozzle. The organic solution was pumped through the inner part of the nozzle, while the CO2 went through the external route. Improved mixing between the two
Figure 3. Amoxicillin particles before SAS treatment.
flows was achieved because of the geometry of the nozzle. During the introduction of the organic solution, the active substance precipitated and could be visually observed as a fine white cloud. The sample was collected on the filters in powder form. The flow of organic solution was maintained for 15 min to ensure that enough material was collected for analysis. After this, the solution feed was stopped while CO2 flow was kept constant for another 40 min and under the same conditions of pressure and temperature in order to wash the formed particles and remove any residual solvent that would dissolve them upon depressurization. After washing, the vessel was gradually depressurized to atmospheric conditions, although collection of the particles was possible without depressurizing the entire system since the filters could be isolated from the rest of the system. After depressurization, the DMSO was collected in the extraction vessel while the CO2 was vented to the atmosphere through the flow meter. The pressure and temperature were kept constant to within (0.2 bar and (0.1 K, respectively. Analytical Methods. Scanning electron microscopy (SEM, JEOL, model JSM-840A) was used for characterizing our particles. Prior to the analysis, the samples were coated with graphite to avoid charging under the electron beam. The mean particle size and morphology were examined and related to the conditions of each individual experiment. Certain images, taken from various areas of the sample, were further analyzed and the sizes of 350 randomly picked microparticles were used in order to determine the size distribution of the powdered samples. In addition, samples were analyzed with a Rigaku Denki X-ray diffraction (XRD) spectrometer in order to determine the effect the SAS process parameters had on the crystallinity of the pharmaceutical substance. Results and Discussion Various experimental protocols were followed for the study of the precipitation process of amoxicillin with supercritical antisolvent. Different external pressures resulted in powders of amoxicillin with different mean particle sizes and size distributions. In addition, different solute concentrations were used over a range of different pressures to study the effect of concentration on mean particle size and size distribution. DMSO was used as organic solvent in the first set of experiments. DMSO is considered a nontoxic solvent and is widely used in SAS experiments. However, it is quite harmful
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Figure 4. SEM images of amoxicillin particles produced from a 2% w/v solution of amoxicillin in DMSO at temperature ) 313.15 K and pressure ) (A) 100 bar, (B) 150 bar, (C) 200 bar, and (D) 250 bar.
Figure 5. Number-based particle size distribution of amoxicillin particles produced from a 2% w/v solution at temperature ) 313.15 K and pressure ) (A) 100, (B) 150, (C) 200, and (D) 250 bar.
Figure 6. Effect of pressure on the mean particle size and size distribution from a 2% w/v solution of amoxicillin at temperature ) 313.15 K, standard deviation reported as vertical bars.
and an attempt was made to replace it with ethanol (EtOH). Experiments were, thus, conducted with a 1% w/v solution concentration of amoxicillin in a 50/50 v/v solution of EtOH/DMSO. The production of micro- and nanoparticles of amoxicillin with this mixed solvent was also successful as will be described below. Effect of Pressure. The first set of experiments involved a 2% w/v solution of amoxicillin in DMSO over a range of pressures ) (100-250 bar). The other operating conditions were: temperature ) 313.15 K; flow rate of organic solution ) 0.07 mL/min; flow rate of carbon dioxide ) 5 SLPM. The lowest pressure employed was 100 bar, high enough however to ensure the complete miscibility between the organic solvent and the supercritical an-
tisolvent. At pressures of about 80 bar, the liquid organic solvent was not entirely miscible with the supercritical CO2, resulting in the formation of liquid rich phase at the bottom of the precipitator. The optical high-pressure windows allowed for these observations, which were also reported by Reverchon et al.12 Each experiment was repeated twice and good reproducibility of the data was obtained. The morphology of the amoxicillin particles before the SAS treatment is shown in Figure 3. It is obvious that raw amoxicillin consists of crystalline rectangular particles with lengths between 5 and 50 µm and a rather broad distribution of widths. A large width of the particle distribution curve means unstable and uncertain kinetics of dissolution of the drug and, thus, unknown properties of the drug.13
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Figure 7. Volume-based particle size distribution of amoxicillin particles produced from a 2% w/v solution at temperature ) 313.15 K and at pressure ) (A) 100, (B) 150, (C) 200, and (D) 250 bar.
The morphology and the size of the particles obtained at various pressures from a 2% w/v concentration solution of amoxicillin in DMSO are reported in Figure 4. The SEM images of the SAS-processed amoxicillin reveals two distinct features. First, the mean size of the amoxicillin particles has been significantly reduced, and second, the morphology of the produced particles has changed from rectangular needlelike to well-defined spheres. The SEM images were analyzed by measuring 350 randomly picked particles. The mean size, the size distribution, and the standard deviation were calculated from the obtained data and correlated with the experimental parameters. Figure 5 shows the size distribution curves of the particles produced at pressure ) 100, 150, 200, and 250 bar. At elevated pressures of 250 and 200 bar, the mean particle sizes were found to be 0.86 and 0.80 µm,
respectively. At 150 bar, however, a shift in behavior is noted as the produced particles were of mean sizes of 0.49 and 0.50 µm at 150 and 100 bar, respectively. Moreover, the standard deviation of the particle sizes is reduced with the reduction of pressure. The above conclusions are summarized in Figure 6, where the standard deviations are reported as vertical bars. From Figures 4-6, two main conclusions are drawn. First, at elevated pressures of 250 and 200 bar, the mean particle size and the standard deviation are almost twice those of the particles produced at 150 and 100 bar. Moreover, at 250 and 200 bar, the measurements of the particle sizes revealed the existence of two different populations of particles from the size point of view: The mean size of the major population was measured to be around 0.5 µm, while that of the other population was measured to be around 1.1 µm. This trend seems to gradually disappear with the decrease in pressure. At 250 bar, the population of the larger particles is distinct. However, at 200 bar a reduction in this population is noted. Although the number of the larger particles is quite smaller compared to the rest of the sample, the volume of those particles is significant. It should be mentioned at this point that this total volume is an important quantity for the pharmaceutical industry where the amount of the active substance that is delivered to the recipient is proportional to this volume of the drug particles. The volume-based particle size distributions are broader compared to the numberbased ones since the volume of a sphere is proportional to the cubic power of the diameter. These volumetric distributions are reported in Figure 7. From Figure 7, it is evident that at 250 bar the two different in size populations of particles are more distinct, while the curve at 200 bar exhibits the larger standard deviation since the particle sizes range from 0.4 to 2 µm. At 150 bar there is a notable decrease in
Figure 8. SEM images of amoxicillin particles produced from a 0.5% w/v solution of amoxicillin in DMSO at temperature ) 313.15 K and at pressure ) (A) 150 bar, (B) 200 bar, and (C) 250 bar.
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Figure 9. Number-based particle size distribution of amoxicillin particles produced from a 0.5% w/v solution at temperature ) 313.15 K and at pressure ) (A) 150, (B) 200, and (C) 250 bar.
Figure 10. Volume-based particle size distribution of amoxicillin particles produced from a 2% w/v solution at temperature ) 313.15 K and at pressure ) (A) 150, (B) 200, and (C) 250 bar.
the standard deviation of the particle sizes. The same trend is followed for the particles produced at 100 bar, with the bulk of the material between 0.2 and 1.2 micrometers. This is very important since it proves the ability of the SAS process to control the mean size and size distribution of the particles by simply changing the operating pressure. The shift from mean sizes of about 0.8 µm at elevated pressures to 0.5 µm at lower pressures is attributed to the different solvent strength of the CO2-DMSO mixture at different pressures. Specifically, at elevated pressures the CO2-DMSO mixture is a better solvent for amoxicillin, resulting in smaller degrees of supersaturation in the nucleation stage. This leads to larger sizes of microparticles since a smaller number of nuclei are formed in the nucleation stage, allowing for the material to be spent in the growth stage. Moreover, because of the smaller number of nuclei, compared to those formed at lower pressures, some of the particles grow to larger diameters, leading to the observed two population profiles. Similar observations were noted for hydrocortisone by Velaga et al.14 As already mentioned, at the lower pressures of 150 and 100 bar, a shift in behavior is noted. In this case, the smaller mean sizes and the lack of larger particles are due to the smaller solvent strength of the CO2-DMSO mixture. The bulk
Figure 11. Effect of pressure on the mean particle size and size distribution of particles produced from a 0.5% w/v solution of amoxicillin in DMSO at temperature ) 313.15 K. The standard deviations are reported as vertical bars.
Figure 12. Effect of concentration (C, % w/v) on the mean particle size and size distribution for particles produced at pressure ) 200 bar and temperature ) 313.15 K. Standard deviations reported as vertical bars.
of the amoxicillin is spent in the nucleation stage, resulting in an increased number of nuclei and a reduced quantity of amoxicillin to be spent in the growth stage. Smaller particles are thus produced with a smaller standard deviation. Shekunov et al.11 have studied the effect that the decrease of supersaturation, due to the increase in pressure and thus the increase of the solvent power of the modified CO2-organic solvent mixture, may have on the characteristics of the microparticles extensively. Their findings were similar to those that are presented in this work; high pressures may result in the decrease of supersaturation, which has an immediate effect on the mean size of particles and their standard deviations. To further study the effect of pressure, another set of experiments was conducted. In this second set, a 0.5% w/v solution of amoxicillin was employed. Microparticles were produced at pressures ) 250, 200, and 150 bar. Figure 8 presents the SEM images obtained from the correspondent samples. Once again, the sizes of 350 randomly picked particles were measured. The number- and volume-based particle size distributions are presented in Figures 9 and 10, respectively.
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Figure 13. SEM images of amoxicillin particles produced from a 1% w/v solution of amoxicillin in 50/50 v/v DMSO/EtOH mixture at temperature ) 313.15 K and at pressure ) (A) 100 bar, (B) 150 bar, (C) 200 bar, and (D) 250 bar.
As before, the dual population profile is evident at 250 bar. However, in this case the above shift in behavior is noted at 200 bar. This is a consequence of the reduced concentration of the organic solution, which does not allow for the growth of larger microparticles. Moreover, the mean particle sizes are smaller, as are their standard deviations. Figure 11 summarizes these observations. Figures 6 and 11 reveal the potential of the SAS process to control the mean size and size distribution of the produced particles, allowing therefore for the production of particles with specific, well defined and controlled properties of the pharmaceutical substance. Effect of Solution Concentration. To further study the effect of concentration, the intermediate solution concentration of 1% w/v was studied at pressure ) 200 bar. The pressure of 200 bar was chosen because it seems to be a transitional point for the size-distribution profiles. The mean particle sizes and their corresponding standard deviations are reported in Figure 12 for particles produced at 200 bar, 313.15 K, and for solution concentrations of 0.5, 1, and 2% w/v of amoxicillin in DMSO. As mentioned before, it is evident from Figure 12 that a reduction in solution concentration results in a reduction in the mean particle size and in the standard deviation. Another parameter that allows for the control of the produced particles is therefore the solution concentration. Reverchon et al.7 have made the same observations for the effect that the concentration of amoxicillin in the NMP organic solution has on the mean sizes of the produced microparticles. Effect of Solvent. DMSO is a nontoxic, nonflammable substance, much more attractive compared to NMP, which was used by Reverchon et al.7 for the production of amoxicillin microparticles. However, although it is widely used, it is considered harmful, a property that poses a disadvantage for its use in the pharmaceutical industry.15 An
attempt was therefore made to replace it in part by the less harmful EtOH. For this purpose, 1 g of amoxicillin was dissolved in a mixture of 50 mL of DMSO and 50 mL of EtOH. A series of experiments was conducted with this mixed solvent at temperature ) 313.15 K and at pressure ) (100-250 bar). Images of the produced particles are reported in Figure 13. Once more particles of the micro- and the nanoscale are successfully produced. A comparison with those produced from DMSO reveals a slight tendency for coalescence. It should be noted that EtOH is a poor solvent of amoxicillin, therefore the 1% w/v solution in 50/50 v/v DMSO/EtOH should be compared to the 2% w/v solution of amoxicillin in DMSO. DMSO was thus successfully partly replaced with a less harmful and more appropriate for pharmaceutical processing solvent. Figure 14 presents the number-based particle size distribution of these particles. It is noted that both the mean particle size and the standard deviation are further decreased. Table 1 presents these data. It is noted that, in the case of the EtOH/DMSO mixture, the effect of pressure is inverse to that observed for the DMSO solutions. Increasing pressure results in the decrease of the mean particle size for medium to high pressures. At 200 bar, a minimum of 0.35 µm mean diameter size is noted with a 0.12 standard deviation. A further increase of the pressure at 250 bar produces particles of 0.4 mean size and 0.16 standard deviation. The change in the pressure effect can be attributed to the change of the solvent power of the organic solution. Because ethanol is a poor solvent of amoxicillin and because it comprises 50% of the organic solvent, the CO2-EtOH-DMSO mixture does not dissolve amoxicillin as was the case for the CO2DMSO binary mixture. This in turn results in greater degrees of supersaturation leading to smaller mean sizes and standard deviations. At 250 bar however, the
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Figure 14. Number-based particle size distribution of amoxicillin particles produced from a 1% w/v solution in 50/50 DMSO/EtOH at temperature ) 313.15 K and at pressure ) (A) 100, (B) 150, (C) 200 bar, and (D) 250 bar.
Figure 15. Number-based particle size distribution of amoxicillin particles produced from a 1% w/v at temperature ) 313.15 K, pressure ) 250 bar, and from (A) 50/50 v/ v DMSO/EtOH and (B) 50/50 v/v DMSO/MeOH.
Table 1. Mean Sizes and Standard Deviations of Microparticles Produced from a 1% W/v Amoxicillin Solution in 50/50 v/v DMSO/EtOH P (bar)
mean size (µm)
standard deviation
100 150 200 250
0.43 0.4 0.35 0.4
0.12 0.12 0.12 0.16
pressure is high enough so that even the CO2-EtOHDMSO mixture regains some of its solvent power, reducing the supresaturation and thus increasing the mean size and the standard deviation of the produced particles. To ascertain these allegations another experiment was run at 250 bar, this time replacing ethanol with methanol. Again the solution was 1% w/v solution in 50/50 DMSO/MeOH. Methanol has similar properties with ethanol and the same polar, small molecule. However, the solubility of amoxicillin in ethanol is 3.4 mg/mL, whereas in methanol it is 7.5 mg/mL.17 Therefore, the CO2-MeOH-DMSO mixture, would be expected to have a stronger solvent power toward amoxicillin, compared to the CO2-EtOH-DMSO mixture, which would result in a further decrease of the supersaturation and thus a further increase in the mean particle size. Figure 15 presents a comparison of the number-based distributions of the particles produced at 250 bar from the two different solvent mixtures. An increase in the mean size from 0.4 to 0.5 is noted, confirming the effect that the solvent has on the production of amoxicillin particles. To further clarify the effect that the SAS treatment has on amoxicillin, XRD patterns of it were obtained before and after SAS treatment. Amoxicillin was crystalline before the treatment with supercritical antisolvent and became amorphous after SAS as inferred from Figure 16. Reverchon et al.7 has also made this observation and attributed it to the speed of the crystallization process in SAS, which does not allow for the organization of the solute in crystalline form. Since amoxicillin is not easily soluble in water, the production of the more soluble amorphous material is a significant advantage. Amorphous drugs are not, however, as stable as the crystalline ones, and thus the stability of the amorphous material must be taken into consideration.
Figure 16. XRD patterns of amoxicillin before and after SAS treatment. Upper trace, unprocessed; lower trace, SAS processed.
Conclusions By use of the SAS process, we were able to produce micro- and nanoparticles of amoxicillin from a DMSO solution, a solvent by far less toxic than NMP, which has been used in the literature for the same purpose. It was shown that the mean particle size and the standard deviation are controllable by varying either the concentration of the organic solution or the pressure of the system. Thus, with appropriate conditions one may produce particles with size distributions that allow for the pulmonary delivery of the drug or the production of injectable suspensions.16 Overall, the mean particle size was reduced down to values of 0.5 and 0.8 µm in the case of the employment of DMSO as a solvent, allowing for the increase of the specific area of the material and, consequently, its solubility. In addition, an attempt was made to partly replace DMSO with EtOH and MeOH, two less harmful organic solvents. Particles of mean size 0.35 µm were produced with a slight tendency for coalescence. Work is underway in our Laboratory that explores the possibility for further replacement of DMSO by EtOH, along with the effect of higher concentrations of organic solution and the effect of temperature on the morphology of the produced particles. The understanding of the effects of these parameters is
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crucial in the design of the next step in microparticle production, which is the microencapsulation of the drug in a biodegradable matrix. Acknowledgment Financial support for this work has been provided by the Greek GSRT/PENED 2001. Literature Cited (1) Gallagher, P. M.; Coffey, M. P.; Krukonis, V. J.; Hillstrom, W. W. Gas anti-solvent recrystallization of RDX: formation of ultra-fine of a difficult-to-comminute explosive. J. Supercrit. Fluids 1992, 5, 130-142. (2) Reverchon E. Supercritical antisolvent precipitation of micro- and nanoparticles. J. Supercrit. Fluids 1998, 15, 1-21. (3) Subra, P.; Jestin, P. Powders elaboration in supercritical media: comparison with conventional routes. Powder Technol. 1999, 103, 2-9. (4) Gonda I. Pharmaceutics: The Science of Dosage Form Design; Aulton, M. E., Ed.; Churchill Livinstone, 1988. (5) Altiere, R. J.; Thompson, D. C. Inhalation Aerosols, Series Lung Biology in Health Disease; Hickey, A. J., Ed.; New York, 1996; Vol. 94, p 5. (6) Mobley, C.; Hochhaus G. Methods used to assess pulmonary deposition and absorption of drugs. Drug Discuss. Today 2001, 6, 367-375. (7) Reverchon, E.; Della Porta, G.; Favilene, M. G. Process parameters and morphology in amoxicillin micro and submicro particles generation by supercritical antisolvent precipitation. J. Supercrit. Fluids 2000, 17, 239-248. (8) Kalogiannis K.; Lambrou, Ch.; Lee, Y.-W.; Panayiotou, C. Paracetamol micronization by precipitation with the SAS/SEDS
process: Influence of process parameters. Presented at the 6th International Symposium on Supercritical Fluids, Versailles, France, 2003. (9) Hanna, M. H.; York, P. Particle engineering by supercritical technologies for powder inhalation drug delivery. In Proceedings of the Respiratory Drug Delivery Conference V, Phoenix, AZ, 1996. (10) Palakodaty, S.; York, P.; Pritchard, J. Supercritical fluid processing of materials from aqueus solutions: the applications of SEDS to lactose as a model compound. Pharm. Res. 1998, 15, 1835. (11) Shekunov, B. Yu.; Hanna, M.; York, P. Crystallization process in turbulent supercritical flows. J. Cryst. Growth 1999, 198/199, 1345. (12) Reverchon, E.; De Marco, I.; Della Porta, G. Rifampicin microparticles production by supercritical antisolvent precipitation. Int. J. Pharm. 2002, 243, 83-91. (13) York, P. Strategies for particle design using supercritical fluid technologies. Pharm. Sci. Technol. Today 1999, 11, 430-440. (14) Velaga, P. S.; Ghaderi, R.; Carlfors, J. Preparation and characterisation of hydrocortisone particles using a supercritical fluids extraction process. Int. J. Pharm. 2002, 231, 155-166. (15) Sze Tu, L.; Dehghani, F.; Foster, N. R. Micronisation and microencapsulation of pharmaceuticals using a carbon dioxide antisolvent. Powder Technol. 2002, 126, 134-149. (16) Muˆller, R. H.; Peters, K. Nanosuspensions for the formulation of poorly soluble drugs I. Preparation by a size reduction technique. Int. J. Pharm. 1998, 160, 229-237. (17) Merck index, 1996, 97.
Received for review June 7, 2005 Revised manuscript received September 2, 2005 Accepted September 19, 2005 IE050654M
