Exploring High Operating Conditions in the Ibuprofen Precipitation by

Article pubs.acs.org/IECR

Exploring High Operating Conditions in the Ibuprofen Precipitation by Rapid Expansion of Supercritical Solutions Process A. Montes,* A. A. Litwinowicz, U. Gradl, M. D. Gordillo, C. Pereyra, and E. J. Martínez de la Ossa Department of Chemical Engineering and Food Technology, Faculty of Sciences, University of Cádiz, International Excellence Agrifood Campus (CeiA3), 11510 Puerto Real, Cádiz, Spain ABSTRACT: Micronization of ibuprofen by a rapid expansion of supercritical solutions (RESS) process has been explored for a wide range of operating conditions, including temperatures above the melting point of ibuprofen. Morphologies, particle sizes (PSs), and particle size distributions (PSDs) have been analyzed by scanning electron microscopy and the crystallinity has been evaluated by X-ray diffraction measurements. Possible structural changes in the drug after supercritical fluid processing were evaluated by Fourier transform infrared spectroscopy. The effects of different pressures (100−350 bar), temperatures (308−353 K), and nozzle diameters (100−200 μm) on the drug precipitation have also been investigated. The morphology of the precipitated particles was improved in the majority of cases in comparison to the raw material, and the PS decreased. In general, higher pressures led to smaller particle sizes. The smallest particle sizes were obtained at 318 and 333 K, and precipitated powder was obtained even at temperatures above the melting point of ibuprofen. A larger nozzle diameter led to a larger particle size.

1. INTRODUCTION Pharmaceutical preparations are the final products of a technological process that gives the drugs the appropriate characteristics for easy administration, proper dosage, and enhancement of the therapeutic efficacy. The very poor aqueous solubility and wettability of the majority of particulate and solid drugs give rise to difficulties in the design of pharmaceutical formulations.1 The bioavailability of poorly water-soluble drugs present in a solid formulation depends strongly on the particle size (PS), the particle size distribution (PSD), and the morphology of the particles.2 The dissolution rate is the limiting factor for the drug absorption rate.3 This rate can be enhanced significantly by reducing the particle size, and, as a consequence, there is increasing interest in the development of efficient size-reduction processes. Conventional techniques suffer from several drawbacks such as excessive use of solvent, thermal and chemical solute degradation, structural changes, high residual solvent concentration, and, most importantly, difficulty in controlling the PS and PSD during processing. Supercritical fluid (SCF) technology has emerged as an important alternative to traditional processes for the generation of micro- and nanoparticles.4−6 This approach offers opportunities and advantages such as higher product quality in terms of purity, more uniform dimensional characteristics, the variety of compounds that can be processed, and a substantial improvement in relation to environmental considerations, among others. Moreover, supercritical conditions are sufficiently mild to permit the micronization of thermolabile solutes. Of all possible SCFs, carbon dioxide (CO2) at supercritical conditions is the most widely used due to its relatively low critical temperature (304.1 K) and pressure (73.8 bar), low toxicity, and low cost. The properties of SCFs (solvent power and selectivity) can also be adjusted continuously by altering the experimental conditions (temperature and pressure). These properties make such fluids excellent media in which to dissolve organic © 2013 American Chemical Society

materials, especially for processing pharmaceutical compounds by the rapid expansion of supercritical solutions (RESS).1,2,7−26 In the RESS method, the sudden expansion of a supercritical solution (solute dissolved in supercritical carbon dioxide) through a nozzle and the rapid phase change at the exit of the nozzle causes a high level of supersaturation, which in turn causes very rapid nucleation of the substrate in the form of very small particles that can be collected from the gas stream. Temperatures within the solubilization chamber should be lower than the melting point of the solute in order to avoid the existence of a solute liquid phase in the precipitation process. In the study described here, ibuprofen was considered as a model drug for precipitation by the RESS process. Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) that has analgesic and antipyretic effects and, in higher doses, antiinflammatory effects. This drug is widely used in many applications. The high solubility of ibuprofen27 in supercritical CO2 means that it cannot be processed by a supercritical antisolvent (SAS) process, and RESS or particle from gas saturated solutions (PGSS) processes are recommended. The aim of the work described here was to study the precipitation of ibuprofen by an RESS process in order to identify new operating conditions to obtain particles as small as possible in the micro- or nanometer ranges. A further aim was to establish the crystallinity and chemical stability of ibuprofen particles after the RESS process. In addition, the effects of the RESS parameterssuch as solubilization pressure and temperature, and nozzle diameteron the size and morphology of the ibuprofen particles were investigated. Temperatures within the solubilization chamber above the melting point of ibuprofen were assayed in order to evaluate the operation limits of the Received: Revised: Accepted: Published: 474

July 26, 2013 November 26, 2013 December 10, 2013 December 10, 2013 dx.doi.org/10.1021/ie402408j | Ind. Eng. Chem. Res. 2014, 53, 474−480

Industrial & Engineering Chemistry Research

Article

Figure 1. Schematic diagram of the RESS250 pilot plant.

thermocouples placed inside (V1-TS2) and outside (V1-TS1) the solubilization chamber, on the nozzle (N1-TS3), and on the electric high-pressure heat exchanger to obtain continuous temperature measurements; a FlexCOR coriolis mass flowmeter (FM1) to measure the CO2 mass flow rate. A 5 μm filter (F1) was fitted at the exit of the solubilization chamber to ensure that during expansion of the solution undissolved ibuprofen particles would not be carried over with the supercritical CO2 flow. All factors that have an influence on the precipitation process (temperature, flow rate, and pressure, etc.) were controlled automatically (using ICM software). A particularly important component of the RESS250 system is the nozzle that sprays the supercritical solution into the precipitator vessel (V2). Stainless steel nozzles from Thar Technologies with an inner diameter between 100 and 200 μm and a length of 1170 μm were used in this work. All experiments were performed by following the same procedure. First, the ibuprofen powder was placed into the solubilization cell. The cell was closed, and CO2 was pumped into this chamber at the same time as the electrical heater and heat exchanger were switched on. Once CO2 supercritical conditions (pressure and temperature) had been achieved, the conditions were maintained for 1 h to ensure that complete equilibrium had been reached. The valve MV2 was opened, and the supercritical solutions were expanded through a preheated nozzle. This nozzle was preheated to 333 K in order to compensate for the heat loss and to prevent the nozzle from clogging during expansion. The precipitated particles were collected on the wall of vessel V2 for subsequent analysis. Racemic ibuprofen with a melting point of 349 K was purchased from Sigma-Aldrich (Madrid, Spain). CO2 with a minimum purity of 99.8% was supplied by Linde (Jerez, Spain). The mean particle size of commercial ibuprofen was about 94 ± 39 μm. Scanning electron microscopy (SEM) images of the raw and precipitated materials were obtained using a SIRION scanning electron microscope. Prior to analysis, the samples were placed

RESS process. In cases where this approach was successful, the influence of the existence of an ibuprofen liquid phase on the morphology, particle size, and particle size distribution of the precipitated drug was evaluated. Hezave and Esmaeilzadeh1 obtained particles with a wide range of diameters from 880 to 6.72 μm; Charoenchaitrakool et al.9 obtained particles in the micrometer range (2.75−7.48 μm), and Kayrak et al.11 obtained even smaller particles (2.5 μm) under relatively mild operating conditions. Chen et al. used a polymer in a PGSSbased method to produce less agglomerated ibuprofen nanoparticles in the nanometer range.28 Nanoparticles were also obtained in this investigation by an RESS process over a wide range of operating conditions, even at temperatures above the melting point melting of ibuprofen: the solid−liquid−gas (SLG) line for the CO2/ibuprofen system follows those obtained in experiments performed at 333 and 353 K, where a liquid/vapor equilibrium exists.9

2. MATERIALS AND METHODS The experiments were carried out in a pilot plant developed by Thar Technologies (model RESS250). A schematic diagram of this equipment is shown in Figure 1, and the details are given in a previous publication.29 The RESS250 system comprises the following main components: a high-pressure pump for the CO2 (P1); a 250 mL stainless steel solublization chamber (V1) surrounded by an electrical heating jacket (V1-HJ1); a magnetic stirrer (maximum speed, 2500 rpm) to hold the solute and supercritical CO2 in continuous mixing, and a stainless steel collection vessel (V2) where particles are precipitated. The following auxiliary elements were also necessary: a low-pressure heat exchanger (HE1); cooling lines, and a cooling bath (CWB1) to keep the CO2 inlet pump cold and to chill the pump heads; an electric highpressure heat exchanger (HE2) to preheat the CO2 in the solubilization chamber to the required temperature quickly; safety devices (rupture discs and safety valves MV1 and MV2); pressure gauges for measuring the pump outlet pressure (P1, PG1) and the solubilization chamber pressure (V1, PG1); 475

dx.doi.org/10.1021/ie402408j | Ind. Eng. Chem. Res. 2014, 53, 474−480


Article

3. RESULTS AND DISCUSSION All of the experiments led to the successful precipitation of ibuprofen on the wall of the upper part of the collection vessel. These experiments included conditions on the left-hand side of the SLG line, where a solid/fluid two-phase equilibrium exists for each pressure, and those on the right-hand side of this line, where a liquid/vapor equilibrium exists (Figure 2).9 SEM

on carbon tape and then covered with a coating of gold using a sputter coater. SEM images were processed using Scion image analysis software (Scion Corp.). PS and PSD were then calculated using Statgraphics plus 5.1 software. More than 200 particles were counted to carry out the analysis in each experiment. PSDs were represented as probability density functions. The crystallinities of RESS-processed and unprocessed ibuprofen were evaluated using an X-ray powder diffractometer (XRD, Bruker, D8 ADVANCED, Karlsruhe, Germany). The sample was irradiated using a Cu target tube and exposed to monochromatic radiation. The scanning angle ranged from 5 to 100° of the diffraction angle (2θ), and the counting time used was 1 s/step in steps of 2θ = 0.05°. The excitation current was 40 mA, and the excitation voltage was 40 kV. Fourier transform infrared (FTIR) spectroscopy was performed on a FTIR Bruker Tensor 37 spectrophotometer with a spectral resolution of 0.6 cm−1 in order to analyze possible structural changes to the ibuprofen after the RESS process. The transmittance measurements were carried out according to the KBr technique using potassium bromide pellets containing 1% by weight of silica powder. The spectra were collected in the 400−4000 cm−1 range. The different operating conditions used in the precipitation experiments are summarized in Table 1 together with the

Figure 2. Pressure−temperature diagram of the three-phase SLG line for the ibuprofen/carbon dioxide system (adapted from Charoenchaitrakool et al.9. Copyright 2000 American Chemical Society.). Numbers corresponding to some experiments shown in Table 1 have been included.

Table 1. Experimental Program and Quantitative Results of Particle Size runs

P (bar)

T (K)

nozzle diam (μm)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

100 150 200 250 300 100 150 200 250 300 350 150 200 250 300 350 100 200 300 200 200

308

100

318

333

353

308

150 200

images of the raw and precipitated materials in powder form are shown in Figures 3−6. In general, the morphology of the precipitated powder particles was different from that of raw material and a quasi-spherical morphology was observed for most products.

PS (μm) 1.29 1.26 1.17 1.34 0.69 1.04 0.67 0.35 0.27 0.22 0.23 0.34 0.38 0.32 0.15 2.21 1.37 1.93 2.65 1.93 1.72

± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±

0.38 0.58 0.44 0.57 0.31 1.48 0.38 0.18 0.08 0.06 0.04 0.11 0.17 0.15 0.02 0.87 0.63 0.82 1.20 0.93 1.16

Figure 3. SEM image of unprocessed ibuprofen.

However, the use of the RESS process led to a reduction in particle size by more than 100 times. The results are shown in Table 1, and it can be seen that PSs in the 0.150−2.65 μm range were obtained. PSD results are represented as probability density functions (Figures 4−6). It is worth noting that the smallest PS and narrowest PSD were achieved at 300 bar and 318 and 333 K and the worst case (largest PS and largest PSD) was for the particles processed at 300 bar at 353 K (temperature far above the melting point of ibuprofen at that pressure). Hezave and Esmaeilzadeh,1 Charoenchaitrakool et al.,9 and Kayrak et al.11 precipitated particles of ibuprofen by an

results obtained. Changes in the pressure and temperature in the solubilization chamber led to changes in the amount of drug solubilized in the supercritical phase, which in turn modified the amount of drug being precipitated. The effect of high temperatures within the solubilization chamber, where an ibuprofen liquid phase coexists, on the morphology and size was explored. The results are discussed in detail in the appropriate section. 476



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Figure 4. SEM images of ibuprofen precipitated particles at 318 K by RESS process: pressure effect. Curves of the probability density function for particle size distribution are shown in the insets.

Figure 5. SEM images of ibuprofen precipitated particles at 300 bar by RESS process: temperature effect. Curves of the probability density function for particle size distribution are shown in the insets.

RESS process in the ranges of 880 nm to 6.72 μm, 2.75 to 7.48 μm, and less than 2.5 μm, respectively, but in these cases low temperatures were used. According to our PS data, the

precipitation of ibuprofen nanoaparticles (150 nm; run 15) could even be achieved at relatively high pressure and 477



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Figure 6. SEM images of ibuprofen precipitated particles at 200 bar and 308 K by RESS process: nozzle diameter effect. Curves of the probability density function for particle size distribution are shown in the insets.

concluded that the dimensions of particles decrease on increasing the operating pressure. At 308 K the particle size seems to be independent of the pressure. Similarly, a clear dependence of the particle size, or a lack of sensitivity to this parameter, was not observed for solubilization pressure by other authors.11 The largest particle size was obtained at the highest solubilization pressure at 333 K. Such a contradictory result has also been obtained by other authors with respect to the influence of the pressure on PSs: Huang et al.,8 Turk and Bolten,24 Wang et al.,25 and Yildiz et al.26 found that the particle size increased upon increasing the pressure. This fact can be explained because under these operating conditions the particle growth may be dominant over nucleation or a particle may include several nuclei during the growth process at a particular pressure.8 These results indicate how difficult it is to establish general rules to describe the behavior of these complex systems. The effect of solubilization temperature on particle size and morphology was determined over the temperature range of 308−353 K. Experiments at temperatures above the melting point of ibuprofen were carried out in order to evaluate the influence of the presence of a liquid phase in the RESS micronization. In each series of experiments the rest of the operating conditions were kept constant. In general, an increase in the extraction temperature at different pressures (100, 150, 200, 250, 300, and 350 bar) led to a decrease in the PS (see Figure 5). Increases in the extraction temperature lead to a decrease in the density of CO2 and a concurrent increase of the solute vapor pressure, so there are two competing phenomena: a decrease in the solvent strength and an increase in the drug solubility.1 In the work described here, the increase in drug solubility prevailed and higher supersaturations were achieved, which in turn gave rise to smaller PS. It is worth noting that the

temperature; i.e., on the right-hand side of the SLG line, where a liquid/vapor equilibrium exists for each pressure. The effect of the pressure in the solubilization chamber on the size and morphology of the resulting particles was tested at different levels (150, 200, 250, 300, and 350 bar) while the other parameters were held constant. The results are given in Table 1. The SEM images and the quantitative results are shown in Figure 4 and Table 1. In general, the particle size decreased as the pressure increased. If we consider the 318 K series, at 100 bar the particle size is larger (1.04 ± 1.48 μm) than at 300 bar (0.22 ± 0.06 μm) or 350 bar (0.23 ± 0.04 μm). Even at 333 Kwhere the existence of an ibuprofen liquid phase at relatively low pressure could influence the supersaturation of the supercritical solutionnanoparticles were obtained at 300 bar (0.15 ± 0.02 μm). Anyway the melting point could even increase at a pressure higher than 250 bar30 by carrying out the process from a solid phase. The morphology remained unaltered as sticky particles were obtained up to 200 bar, but at the highest pressure quasispherical particles are also produced. In this way, Hezave and Esmaeilzadeh1 generally obtained precipitated ibuprofen particles with irregular shapes but some of the precipitated particles were close to spherical in form. The effect of extraction pressure on the PS of the precipitated particles can be explained because when the extraction pressure is increased, the density of the supercritical fluid would also increase. This change would enhance the solvating power of the supercritical fluid and therefore the solute concentration in the SCF. According to the classical theory of nucleation, higher supersaturation brings about a higher nucleation rate during the expansion period and this ultimately leads to the generation of smaller particles. Similar results were obtained by several authors,1,7,20,23 and it was 478



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the crystallinity of the RESS-processed samples was unaltered even at the highest solubilization temperature. FTIR spectra of the RESS-processed samples of ibuprofen were obtained in order to assess the possible degradation of the drug. It can be seen from Figure 8 that the spectrum of

melting point of ibuprofen decreased from 349 K at ambient pressure to 318 K at 180 bar,9 and, as a result, at 333 K a liquid phase would exist for ibuprofen. However, in this case particles in the nanometer range were obtained at 300 bar and 333 K. The highest particle size was obtained at 353 K. At this temperature ibuprofen is far above its melting point on the right-hand side of the SLG line (Figure 2). In this case the existence of ibuprofen as a liquid rather than as a solid phase makes it difficult to achieve supersaturation of the supercritical solution. This situation leads to the precipitation of agglomerated particles, which are larger in size. The particle morphology does not appear to have a clear dependence on extraction temperature. The effect of nozzle diameter on the characteristics of the precipitated particles was determined through experiments 3, 20, and 21 shown in Figure 6. Comparison of the results of these experiments shows that a larger nozzle diameter led to larger PS, although the particle morphologies obtained in these runs were similar. Pharmaceutical compounds are exposed to changes in pressures, temperatures, and relativity humidity during most pharmaceutical processes, and this fact can cause defects in their crystal lattice and decrease of the degree of crystallinity.11 The crystallinity of a drug has an effect on its bioavailability and on its chemical and physical stability, so a loss of crystallinity could have a detrimental effect on the activity of the drug. The XRD patterns of unprocessed ibuprofen and RESS-processed samples are shown in Figure 7. It can be seen from this figure that similar X-ray diffraction patterns were obtained for the raw material and the precipitates obtained by the RESS process; i.e.,

Figure 8. FTIR of unprocessed and RESS-processed ibuprofen.

ibuprofen is very complex, especially in the lower wavenumber region. RESS-processed samples show the same bands as the commercial ibuprofen sample. The peaks at 1721 and 2955 cm−1 correspond to the stretching of O−H and CO bonds, respectively, of the propanoic acid −COOH group in the ibuprofen molecule.31 These two peaks remained virtually unchanged after processing. For instance, there is no evidence of salt formation, which would be indicated by a shift in the carbonyl peak from 1721 cm−1 (free carboxyl group) to 1592 cm−1 (carboxylate group).32 The temperature of the process does not affect the chemical stability of ibuprofen even at 353 K, i.e., above its melting point.

4. CONCLUSION All of the experiments carried out in this study led to a successful precipitation of ibuprofen particles by an RESS process over a wide range of operating conditionseven far above the melting point of ibuprofen. Most particles obtained were in the micrometer range (220 nm to 2.65 μm). Nanoparticles (150 nm) with the narrowest particle size distribution were precipitated at 300 bar and 333 K, near the melting point of ibuprofen because of the high pressure.

Figure 7. XRD patterns of unprocessed and RESS-processed ibuprofen. 479



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particles Produced by the Rapid Expansion of Supercritical Solutions and by Spray-Drying. Pharm. Dev. Technol. 2003, 8, 11. (15) Van Nijlen, T.; Brennan, K.; Van den Mooter, G.; Blaton, N.; Kinget, R.; Augustijns, P. Improvement of the dissolution rate of artemisinin by means of supercritical fluid technology and solid dispersions. Int. J. Pharm. (Amsterdam, Neth.) 2003, 254, 173. (16) Alessi, P.; Cortesi, A.; Kikic, I.; Foster, N. R.; Macnaughton, S. J.; Colombo, I. Particle Production of Steroid Drugs Using Supercritical Fluid Processing. Ind. Eng. Chem. Res. 1996, 35, 4718. (17) Chen, Y.-M.; Lin, P.-C; Tang, M.; Chen, Y.-P. Solid solubility of antilipemic agents and micronization of gemfibrozil in supercritical carbon dioxide. J. Supercrit. Fluids 2010, 52, 175. (18) Atila, C.; Yildiz, N.; Ç alimli, A. Particle size design of digitoxin in supercritical fluids. J. Supercrit. Fluids 2010, 51, 404. (19) Chie-Shaan, S.; Muoi, T.; Yan-Ping, C. Micronization of nabumetone using the rapid expansion of supercritical solution (RESS) process. J. Supercrit. Fluids 2009, 50, 69. (20) Asghari, I.; Esmaeilzadeh, F. Formation of ultrafine deferasirox particles via rapid expansion of supercritical solution (RESS process) using Taguchi approach. Int. J. Pharm. (Amsterdam, Neth.) 2012, 433, 149. (21) Hezave, A. Z.; Afta, S.; Esmaeilzadeh, F. Micronization of ketoprofen by the rapid expansion of supercritical solution process. J. Aerosol Sci. 2010, 41, 821. (22) Pourasghar, M.; Fatemi, S.; Vatanara, A.; Najafabadi, A. R. Production of ultrafine drug particles through rapid expansion of supercritical solution; a statistical approach. Powder Technol. 2012, 22, 521. (23) Hezave, A. Z.; Esmaeilzadeh, F. The effects of RESS parameters on the diclofenac particle size. Adv. Powder Technol. 2011, 22, 587. (24) Turk, M.; Bolten, D. Formation of submicron poorly watersoluble drugs by rapid expansion of supercritical solution (RESS): results for Naproxen. J. Supercrit. Fluids 2010, 55, 778. (25) Wang, J.; Chen, J.; Yang, Y. Micronization of titanocene dichloride by rapid expansion of supercritical solution and its ethylene polymerization. J. Supercrit. Fluids 2005, 33, 159−172. (26) Yildiz, N.; Tuna, S.; Doker, O.; Calimli, A. Micronization of salicylic acid and taxol (paclitaxel) by rapid expansion of supercritical fluids (RESS). J. Supercrit. Fluids 2007, 41, 440. (27) Mirzajanzadeh, M.; Zabihi, F.; Arjmand, M. Measurement and Correlation of Ibuprofen in Supercritical Carbon Dioxide Using Stryjek and Vera EOS. Iran. J. Chem. Eng. 2010, 7 (4), 42. (28) Chen, W..; Hu, X.; Hong, Y.; Su, Y.; Wang, H.; Li, J. Ibuprofen nanoparticles prepared by a PGSS-based method. Powder Technol. 2013, 245, 241. (29) Montes, A.; Bendel, A.; Kürti, R.; Gordillo, M. D.; Pereyra, C.; Martínez de la Ossa, E. J. Processing naproxen with supercritical CO2. J. Supercrit. Fluids 2013, 75, 21. (30) Uchida, H.; Yoshida, M.; Kojima, Y.; Yamazoe, Y.; Matsuok, M. Measurement and Correlation of the Solid-Liquid-Gas Equilibria for the Carbon Dioxide + S-(+)-Ibuprofen and Carbon Dioxide +RS(±)-Ibuprofen Systems. J. Chem. Eng. Data 2005, 50, 11. (31) Fengyu, Q.; Guangshan, Z.; Huiming, L.; Weiwei, Z.; Jinyu, S.; Shougui, L.; Shilun, Q. A controlled release of ibuprofen by systematically tailoring the morphology of mesoporous silica materials. J. Solid State Chem. 2006, 179, 2027. (32) Andini, S.; Bolognese, A.; Formisano, D.; Manfra, M.; Montagnaro, F.; Santoro, L. Mechanochemistry of ibuprofen pharmaceutical. Chemosphere 2012, 88, 548.

However, the use of the highest temperature, far above the melting point, gave rise to the largest particles. The use of larger nozzle diameters led to higher particle sizes. In general, the particle size decreased as the pressure and temperature were increased. The morphology of the particles was consistently sticky, but at the highest pressure quasi-spherical nanoparticles were also produced. Similar X-ray diffraction patterns and FTIR spectra were obtained for the raw material and the precipitates obtained by the RESS process. This indicates that the crystallinity was unaltered and the drug was chemically stable under the conditions used.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Fax: +34-956-016-411. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We gratefully acknowledge the Spanish Ministry of Science and Technology (Project CTQ2010-19368) and European Regional Development Fund (ERDF) for financial support.

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REFERENCES

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Exploring High Operating Conditions in the Ibuprofen Precipitation by

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