The effects of RESS parameters on the diclofenac particle size

The effects of RESS parameters on the diclofenac particle size

Advanced Powder Technology 22 (2011) 587–595 Contents lists available at ScienceDirect Advanced Powder Technology journal homepage: www.elsevier.com...

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Advanced Powder Technology 22 (2011) 587–595

Contents lists available at ScienceDirect

Advanced Powder Technology journal homepage: www.elsevier.com/locate/apt

Original Research Paper

The effects of RESS parameters on the diclofenac particle size Ali Zeinolabedini Hezave, Feridun Esmaeilzadeh ⇑ Chemical and Petroleum Engineering Department, School of Engineering, Shiraz University, Shiraz, Iran

a r t i c l e

i n f o

Article history: Received 15 September 2009 Received in revised form 11 August 2010 Accepted 27 August 2010 Available online 9 September 2010 Keywords: RESS parameters Diclofenac Effective nozzle diameter Micronization

a b s t r a c t The RESS method was used to manufacture the fine particles of diclofenac. A reduction in particle size increases the dissolution rate of the drugs in the biological fluids and enhances the bioavailability of them in body. CO2 was used as the supercritical fluid because of its mild critical temperature (31.1 °C) and pressure (7.38 MPa). In this study, effect of extraction temperature (313–333 K), extraction pressure (14–220 MPa), spraying distance (1–10 cm), nozzle length (2–15 mm) and effective nozzle diameter (450–1700 lm) were investigated. Based on the different experimental conditions, the average particle size of diclofenac was between 10.92 and 1.33 lm. The size and morphology of the micronized diclofenac particles were monitored by scanning electron microscopy (SEM). The SEM images show a successful size reduction of virgin diclofenac particles. In all the experiments, the parameters had moderate effect on the mean particle size of the diclofenac. Also, the morphology of the processed particles was change to quasi-spherical and irregular while the virgin particles of diclofenac were irregular in shape. Ó 2010 The Society of Powder Technology Japan. Published by Elsevier B.V. and The Society of Powder Technology Japan. All rights reserved.

1. Introduction Pharma science is witnessing a lot of research targeted at meeting delivery and manufacturing demands of the new age molecules. Entirely new technologies and modifications of existing technologies are being developed to address these needs. Supercritical fluid technology (SFT) has been used in many fields for decades, such as chemical processing, filtration media, food industry, and in the cleaning of precision parts other than pharmaceuticals. Since its fascinating liquid-like density and gas-like transport property, supercritical fluid has been recently explored to micronize organic compounds by rapid expansion of supercritical solution RESS [1]. The rapid expansion of a supercritical solution (RESS) with CO2 as the solvent can produce particles with small mean diameters and narrow size distributions requiring only moderate processing temperature [2–5]. Carbon dioxide is commonly used as a supercritical fluid because it is non-toxic, non-flammable, and cheap. It has a low critical temperature and pressure (Tc = 31.1 °C and Pc = 7.38 MPa) that allow for low temperature processing.

⇑ Corresponding author. Address: Department of Chemical and Petroleum Engineering, Faculty of Engineering, P.O. Box 7134851154, Namazi Square, Shiraz, Iran. E-mail address: [email protected] (F. Esmaeilzadeh).

In addition, carbon dioxide is a naturally occurring chemical that can be recycled from the atmosphere. From a pharmaceutical point of view, supercritical carbon dioxide has several advantages, including being solvent-free, and being able to be used in a singlestage process temperatures. All of these are of the advantage in protecting the environment, in industrial production, and in manufacturing heat-sensitive drugs [6]. The RESS process is consisted of extraction and precipitation units. A substance is dissolved in a supercritical fluid (SCF) at the extraction unit, and then the supercritical solution is suddenly depressurised in a nozzle causing fast nucleation and fine particle formation. Due to the rapid expansion of supercritical solution through a nozzle, the large decrease in density, and hence decreasing the SCF solvating power. The solute becomes supersaturated and then precipitated. The driving force of the nucleation process is super-saturation. High super-saturation leads to increase the nucleation rate and tends to decrease the particles size [7–10]. A decrease in particle size enhances drug solubility, dissolution rate, and drug bioavailability for low solubility drugs [8,11]. In this study, diclofenac was used as the model drug (see Table 1). Diclofenac is an acetic acid non-steroidal anti-inflammatory drug (NSAID) with analgesic and antipyretic properties. Diclofenac is used to treat pain and ocular inflammation, osteoarthritis. Symptoms of overdose include loss of consciousness, and increased intracranial pressure. Depending upon the different experimental conditions, micronized particles of diclofenac in the range of 0.82 and 7.17 lm were obtained.

0921-8831/$ - see front matter Ó 2010 The Society of Powder Technology Japan. Published by Elsevier B.V. and The Society of Powder Technology Japan. All rights reserved. doi:10.1016/j.apt.2010.08.010

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2.2. Particle size and morphology

Table 1 The physiochemical properties of diclofenac drug. Melting point State Average molecular weight Predicted water solubility Molecular formula

The morphology and appearance of surface and the size of the articles examined using scanning electron microscopy (SEM) (S360- CAMBRIDGE). In brief, prior to examination of the samples by SEM the precipitated diclofenac particles were collected on the conductive stubs which were then coated by sputter-coater (SC7640-Polaron) with pd-Pt under the presence of argon (99.9% < purity) at the room temperature for a period of 100 s under an accelerating voltage of 20 kV . The mean particle size, standard deviation, and 95% confidence interval were calculated by a written program which randomly selected 100 particles of the SEM images.

283–285 °C Solid 296.149 4.47E-03 mg/mL C14H11Cl2NO2

2. Methods and materials 2.1. Materials Diclofenac was supplied from Alma Concept Medical Company, France and processed with no further purification. In addition, the CO2 (99.8% < purity) was purchased from Abughadareh Gas Chemical Company, Iran. The mean particle size of the original diclofenac particles was about 38.12 lm, the standard deviation of 7.01 lm and 95% confidence interval of 11.51–39.59 lm with wide particle size distribution. The SEM images and the particle size distribution of the original diclofenac particles are given in Fig. 1.

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The used pilot plant is described in more detail in our previous work [12,13]. The system is consisted of two section; extraction and precipitation section. In each experiment, 4 g of diclofenac powder was packed by glass beads and glass wool in the stainless steel basket. The glass beads were used to increase the effective surface for better mass transfer and prevent channeling phenomena during the experiments. Also, the glass wool was used to prevent carrying undissolved particles of drugs over the SCF flow. At first, CO2 was delivered to the liquefier. The liquefied CO2 was then pumped to the desired pressure by a high-pressure air-driven oilfree reciprocating pump into the vertical surge tank. The surge tank was used to dampen the fluctuation of pressure introduce to the system by the operation of the pump. Both of the surge tank and equilibrium cell was surrounded by the regulating hot water jacket to set the system at the desired temperature. The pressurized SCF was delivered to the equilibrium cell and passed through the packed column of drug powders. The temperature of the equilibrium cell and surge tank could be controlled by a pt-100 controller up to 373 K within ±1 K easily. Also at the outlet of the surge tank, a Bourdon gauge pressure controller with a division of 1 bar up to 400 bar was used which allowed controlling the extraction pressure of the system. After percolating the packed column by SC-CO2, the system was held at the fixed conditions for 2 h to ensure equilibrium was obtained. Then, the SC-CO2 and the dissolved drug powders would be depressurized through a pre-heated fine-needle valve and the drug particles were precipitated in the expansion chamber. The fineneedle valve was heated to prevent clogging caused by the Joule–Thomson effect. 2.4. Nozzle structure

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The used nozzles in this study are combined of two parts, shell part and inside part. More details of the used nozzles and the calculation of the effective nozzle diameter is available in our previous work [12,13].

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2.5. XRD analysis

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2.3. The set up

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101 Particle Size (µm)

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Fig. 1. The SEM images of the original diclofenac particles, (a) the original particles of diclofenac with the magnification of 30, and (b) the particle size distribution of original diclofenac.

The micronized diclofenac particles, forming a weighted dispersion on a glass slide, were evaluated using an X-ray powder diffractometer (Bruker, D8 ADVANCED, Germany). The sample was irradiated using a Cu target tube, and exposed to all lines. A monochromator was used to select the K_1 line (k = 1.54056). The scanning angle ranged from 5° to 100° of the diffraction angle (2h), and the counting time used was 1 s/step in steps of 2h = 0.05°. The scanning rate used was 3o/min. The excitation current used was 40 mA and the excitation voltage used was 30 kV. But, the given XRD figures are reported from 5° to 60° because the remains don’t include any peeks.

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2.6. DSC analysis Thermal analysis of unprocessed and processed diclofenac particles were examined by Mettler Toledo Star SW 9.20 differential scanning colorimeter. In this analysis, approximately 10 mg of sample was heated in the aluminum pan under nitrogen gas flow of 5 mL/min with the heating rate of 10 °C/min and a temperature range of 30–300 °C. 3. Results and discussion In this work, 20 experiments were conducted by changing the RESS process parameters including extraction temperatures (313, 323, 333 K), extraction pressures (14, 16, 18, 200 and 23 MPa), nozzle lengths (2–15 mm), effective nozzle diameter (450–1700 lm) and spraying distances (1, 5 and 10 cm) to investigate the influence of RESS parameters on the size and morphology of the precipitated diclofenac particles. In addition, in all the experiments the pre-expansion temperature was kept equal to the extraction temperature. Based on the different experimental conditions the precipitated particles of diclofenac was in the range of 10.92–2.23 lm while the original particles of diclofenac was about 38.12 lm. Finally, an experiment was conducted with the optimum conditions of different experimental parameters except the nozzle length (see Fig. 2). The obtained particles under the optimum conditions have the smallest mean particle size of the precipitated diclofenac particles (mean particle size of 1.33 lm, standard deviation of 0.26 lm and the 95% confidence interval of 0.36–1.41 lm). In addition, the SEM images show that the RESS process not only is able to micronize the particle of diclofenac but also it is able to modify the morphology of the precipitated particles of the diclofenac particles (some quasi-spherical particles was obtained, see Fig. 3). Moreover, the obtained results show that in the range of our study for pre and post expansion conditions none of the parameters have a dominant effect. Furthermore, the taken SEM images from different experiments show some how homogenous particle formation of diclofenac in size (see Fig. 4). The statistical analyses which are given in Table 2 reveal that last run with optimum conditions has the smallest average particle

Fig. 3. The SEM image of the processed particles (near to spherical form) (Deffective = 900 lm, Textraction = 323 bar, Pextraction = 210 bar, and Lspraying = 1 cm).

Fig. 4. The homogenous particle formation of diclofenac particles during the RESS process.

Table 2 The quantitative results for different nozzle length.

Fig. 2. The homogenous precipitated particles from the last run with the optimum conditions except the nozzle length (Deffective = 450 lm, LNozzle = 5 mm, Textraction = 313 bar, Pextraction = 230 bar, and Lspraying = 1 cm).

Run No.

Lnozzle (mm)

Mean particle size (d50) (lm)

Standard deviation (lm)

95% Confidence interval (lm)

1 2 3 4 5

2 5 8 11 15

10.92 10.16 9.56 8.89 8.36

2.23 2.11 1.77 1.80 1.58

2.72–11.64 2.50–10.98 2.78–9.88 2.35–9.56 2.44–8.78

size, and the smallest standard deviation while run 1 has the largest mean particle size and run 4 has the largest standard deviation. In this study, the XRD patterns and the DSC analysis for the processed and unprocessed diclofenac particles are given in Figs. 4 and 5. The XRD analysis patterns for Fig. 5a and b is nearly at the same angles and the intensity of the peaks is lower for the RESS-SC processed particles of diclofenac which obtained from last run with optimum conditions. Lower intensity can be attributed to the lowering of crystallinity of the particles or change in sample amount. As bulk density of the

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Fig. 5. XRD patterns of (a) unprocessed diclofenac; (b) RESS processed diclofenac particles obtained from last experiment with optimum conditions.

Fig. 6. The DSC analysis of the (a) unprocessed diclofenac, and (b) the RESS processed diclofenac particles obtained from last experiment with optimum conditions.

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RESS-SC processed diclofenac is low so amount of the processed diclofenac is less as compared to the original diclofenac. Formation of the micro-particles can be another reason of lowering of intensity. These obtained results were investigated by DSC analyses which are given in Fig. 6. Coupling the obtained results from DSC and XRD analysis show that the optimum conditions in this study which leads to precipitation of smallest particles in size cause no production of polymorph. But the melting point of the precipitated particles of diclofenac (283.9 ± 0.1 °C) were changed slightly compared with the original particles of diclofenac (279 ± 0.1 °C) which could be related to the experiencing shear forces during the expansion or the re-crystallization and rearrangement of crystalline lattice.

3.2. Effect of the spraying distance Spraying distance from the tip of the nozzle is another important variable which controls the particle size. In these series of experiments, the spraying distance was varied from 1 to 10 cm to investigate the effect of spraying distance while the other including extraction pressure (23 MPa), extraction temperature (323 K), effective nozzle length (1000 lm) and nozzle length (5 mm) were held constant during the experiments.

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3.1. The effect of the nozzle length

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In these experiments, the effect of nozzle lengths (2, 5, 8, 11 and 15 mm) was investigated on the size of the precipitated particles of diclofenac while the other experimental conditions including extraction pressure (21 MPa), extraction temperature (323 K), effective nozzle diameter (900 lm), and spraying distance (1 cm) were held constant during the experiments. The obtained results from these experiments show that an increase in the nozzle length from 2 to 15 mm leads to a decrease in the mean particle size of the precipitated particles from 10.92 to 8.36 lm. The cumulative particle size frequencies of four experiments are given in Fig. 7. Also, it should be mentioned that, the certainty of the obtained trend and this claim that by increasing the nozzle length the mean particle size of the precipitated particles would be decreases is reduces if we consider the standard deviations. But, by investigating the 95% confidence interval, it found that most of the counted particles show the above trend and reveal the size reduction of the precipitated particles with longer nozzle length. This obtained trend for the effect of the nozzle length could be described as follows. Reduction in the length of the capillary causes earlier pressure reduction in the expansion device, even in the upstream of the capillary. Due to earlier start in pressure reduction, more gradual decrease of the pressure is expected rather than in a shorter capillary. A more gradual pressure reduction leads to lower super-saturation and nucleation rates, which results in formation of larger particles. In the literatures, Kayrak et al. [14] reported similar results for the micronization of ibuprofen while contradicting results were obtained for the micronization of the mefenamic acid, ibuprofen and ketoprofen in our previous works [12,13]. Similarly, Wang et al. [15] and Yildiz et al. [8] reported an increase in the mean particle size of the precipitated particles of titanocene dichloride and salicylic acid by increasing the nozzle length. Moreover, they related the increase of mean particle size by increasing the nozzle length to this fact that, when the length of the capillary is smaller, pressure reduction starts earlier in the expansion device, even in the upstream of the capillary. On the other hand, as the pressure reduction starts earlier, more gradual decrease of the pressure is expected instead of a more rapid expansion in the shorter capillary compared to the longer one.

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Particle Size (µm) Fig. 7. The particle size distribution of different nozzle length, (a) run 2, and (b) run 4.

In this section, at glance the obtained results from the mean particles size reveal a reduction in particles size by decreasing the spraying distance. Totally, however, there is uncertainty in the obtained trend in this part, but the obtained results from these three experiments reveal that increasing of the spraying distance from 1 to 10 cm could leads to increase of the mean particle size of the precipitated diclofenac particles. The particle size distribution of the precipitated particles is shown in Fig. 8 and the quantitative results are given in Table 3. The probable trend in this part of study could be related to this description that when the spraying distance is short, the particle growth time is also short and smaller particles are obtained. An increase in distance means an increase in residence time in the expansion chamber which leads to longer particle growth time [8]. Similar results were obtained by Kayrak et al. [14], Wang et al. [15], Yildiz et al. [8], Subra et al. [16] and our previous work [12] for ibuprofen, titanocene, salicylic acid and caffeine and mefenamic acid particles while contradicting results were reported by

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Particle Size (µm) Fig. 8. The particle size distribution of different spraying distances, (a) 1 cm, (b) 5 cm, and (c) 10 cm (Pextraction = 23 MPa, Textraction = 323 K, LNozzle = 5 mm and DEffective = 1000 lm).

Table 3 The quantitative results for different spraying distances. Run No.

Lcollection (cm)

Mean particle size (d50) (lm)

Standard deviation (lm)

95% Confidence interval (lm)

6 7 8

1 5 10

3.64 4.49 5.99

0.74 0.89 1.13

0.90–3.88 1.167–4.73 1.714–6.25

Reverchon et al. [17] and Charoenchaitrakool et al. [18] for salicylic acid and ibuprofen, respectively. 3.3. Effect of extraction pressure and temperature In this study, three series of experiments were conducted to investigate the effect of extraction pressure and temperature on the size and morphology of the precipitated particles of diclofenac. In the first series of experiments, the effect of extraction pressure was investigated by changing it (14, 16, 18, 200 and 23 MPa) while the other parameters including extraction temperature (323 K), nozzle length (5 mm) and spraying distance (1 cm), and effective nozzle diameter (1200 lm) were held constant. The obtained results from the analysis of the SEM images of this series of experiments which are shown in Fig. 9 and Table 4 reveal that an increase in the extraction pressure from 140 to 230 bar leads to a decrease of precipitated particles from 9.04 to 5.09 lm. This ob-

tained trend in the first series of experiments could be explained in this way that, the solvating power of SCF is a function of its density. Higher extraction pressure will cause higher solvating strength. When the solvating power increases, the concentration of the drugs will be increased in SC fluids. Higher drug concentration causes higher super-saturation which leads to smaller size of particles. Similar results were reported by Liu and Nagahama [19] Huang et al. [20], Wang et al. [15], Hezave and Esmaeilzadeh [12] and Hezave et al. [13] and Yildiz et al. [8] for micronization of naphthalene, aspirin, titanocene dichloride, mefenamic acid, ketoprofen, salicylic acid and taxol, respectively. In addition, Reverchon et al. [17] reported contradicting results for micronization of salicylic acid. The extraction temperature could be affects the particle size of the micronized particles by changing the concentration of the solute in the supercritical fluid similar to the extraction pressure. So, in the second and third series of these experiments the effect of extraction temperature on the size and morphology of the precipitated diclofenac particles were investigated by changing the extraction temperature in the range of 313–333 K at the extraction pressure of 20 and 23 MPa while the other experimental conditions including spraying distance (1 cm), nozzle length (5 mm) and effective nozzle diameter (1000 lm) were held constant. The obtained results from the experiments show that an increase in the extraction temperature from 313 to 333 K leads to an increase in the mean particle size of the precipitated particles

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Particle Size (µm) Fig. 9. The particle size distribution of the different extraction pressure, (a) 14 Mpa, (b) 18 Mpa, and (c) 23 Mpa.

Table 6 The quantitative results for different effective nozzle diameter.

Table 4 The quantitative results for different extraction pressure. Run No.

Pextraction (MPa)

Mean particle size (d50) (lm)

Standard deviation (lm)

95% Confidence interval (lm)

Run No.

Deffective (lm)

Mean particle size (d50) (lm)

Standard deviation (lm)

95% Confidence interval (lm)

9 10 11 12 13

14 16 18 20 23

9.04 8.02 7.49 6.09 5.09

1.73 1.63 1.47 1.11 1.03

2.49–9.43 2.07–8.61 2.02–7.91 1.84–6.31 1.28–5.43

20 21 22a 23b 24

450 650 1000 1200 1700

2.23 2.92 3.64 5.09 5.91

0.41 0.60 0.74 1.03 1.30

0.65–2.31 0.71–3.14 0.90–3.88 1.28–5.43 1.32–6.52

a b

Table 5 The quantitative results for different extraction temperature. Run No.

a b

Textraction (K)

Mean particle size (d50) (lm)

Standard deviation (lm)

95% Confidence interval (lm)

Pextarction = 20 MPa 14 313 5.17 15a 323 6.09 16 333 7.25

1.02 1.11 1.51

1.41–5.51 1.84–6.31 1.78–7.84

Pextarction = 23 MPa 17 313 4.44 18b 323 5.09 19 333 5.88

0.90 1.03 1.09

1.17–4.78 1.28–5.43 1.71–6.08

The experimental data of run 12. The experimental data of run 13.

The experimental data of run 6. The experimental data of run 13.

from 5.17 to 7.25 lm for extraction pressure of 20 MPa and from 4.44 to 5.88 lm for the extraction pressure of 23 MPa (see Table 5). The obtained results from these experiments reveal that in the lower extraction pressure (200 bar) the effect of increasing extraction temperature is more evident. This increase in the mean particle size could be related to this fact that, an increase in the extraction temperature causes a decrease in solvent density [8] and a concurrent increase in the solute’s sublimation pressure. Therefore, the net effect of these two competing factors may results in a decrease in the saturated solute concentration in the supercritical fluid if the increase of solute’s sublimation pressure do not compensate the density reduction of SCF by increasing the extraction temperature. The decrease of SCF density decreases

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extraction pressure (23 MPa), nozzle length (5 mm) and spraying distance (1 cm) were held constant while the effective nozzle diameter was ranged from 450 to 1700 lm. The experiments show that the effect of effective nozzle diameter has been reduced at smaller effective nozzle diameter. So, because of the risk of clogging, it is better to use nozzle diameter of 1000 lm. As it is given in Table 6, the results reveal that by increasing the effective nozzle diameter from 450 to 1700 lm, the mean particle size of the precipitated particles of diclofenac was changed from 2.23 to 5.91 lm with a jump in the effective nozzle diameter of 1000 and 1200 lm (also see Fig. 10). This trend could be explain in this way that, decreasing the effective nozzle diameter leads to an increase in the super-saturation and nucleation rate at the tip of the nozzle which means fabrication of smaller particles in size. But, increasing the super-saturation could enhance the risk of coagulation and agglomeration of smaller particles which leads to formation of bigger particles. This description satisfies the obtained results form the experiments which were conducted by different effective nozzle diameters. In the literature, contradicting result was reported by Hernandez et al. [25] and our previous work [12] for the micronization of chitin and mefenamic acid particles, respectively. Similarly, Alessi et al. [26] using nozzles of 30 and 100 lm obtained average sizes of progesterone particles of 4.1 and 7.5 lm, respectively with a closed particle size distribution at minor nozzle diameter.

the solvating strength and solute concentration leads to a decrease in the super-saturation and nucleation rate thus formation of larger size particles. In the literature, similar results have also been reported for mefenamic acid and ketoprofen micronization in our previous works [12,13]. Similarly, Huang et al. [20] and Yildiz et al. [8] for micronization of aspirin and salicylic acid reported that the increase of extraction temperature induced decrease of the particle size, and then increasing temperature resulted in increase of the particle size. In addition, Domingo et al. [21] investigated the micronization of benzoic acid, salicylic acid, phenanthrene and aspirin crystals and reported the effect of extraction temperature only for benzoic acid. 3.4. Effect of the effective nozzle diameter Nozzle configuration had a great effect on the size and morphology of the precipitated particles in SF technology and also, the RESS process. Nozzle is a critical device to fabricate fine particles and its geometry is so vital in the RESS processes. In some literature, instead of nozzle diameter, the nozzle aspect (L/D) has been reported as a greatly effective parameter, considerably for polymers [22–24]. To investigate the influence of the effective nozzle diameter, the other parameters including extraction temperature (323 K),

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Particle Size (µm) Fig. 10. The particle size distribution of different nozzle diameters, (a) 450 lm, (b) 650 lm, and (c) 1700 lm.

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Huang and Moriyoshi [27] achieved a significant reduction of lopeamide HCI particles on the order of 0.3–0.5 lm with nozzle clearance of 5 lm, whereas when using 100 and 200 lm nozzles they obtained particles in an interval of 1–4 lm and 1–7 lm, respectively. Other studies indicate that the size of the nozzle does not cause significant change in the morphology and size of the precipitated, possibly due to the low solubility of the micronized material [28,20]. 4. Conclusions In this study, rapid expansion of supercritical solution (RESS) was used to micronize the diclofenac particles and to investigate the effect of RESS parameters such as, extraction temperature, extraction pressure, nozzle length, effective nozzle diameter and the spraying distance on the size distribution and morphology of the diclofenac particles. The results of the experiments show the success of RESS process to micronize the diclofenac particles. In this study, it was found that, an increase in the extraction temperature, nozzle length effective nozzle diameter and spraying distance will increase the mean particle size of the precipitated diclofenac particles. But other parameter (extraction pressure) had an inverse effect on the mean particle size of the precipitated particles. In the other words, if the extraction pressure increases the mean particle size of the precipitated particles will be decreases. Finally, an experiment was conducted with the optimum experimental conditions except the nozzle length which leads to precipitation of the smallest particles in size among the all experiments conducted in this study. In addition, the XRD and DSC analysis were done to investigate the properties and crystalline characterization of the precipitated particles during the experiment with the optimum conditions which shows that, the precipitated particles was experienced a slight changes in the melting point, heat of fusion and intensity. Also, investigation on the SEM images shows that the precipitated particles of diclofenac were close to the quasi-spherical morphology which reveals the capability of this process to control the morphology of the processed particles. Finally, by considering these results it could be claim that the RESS process has the ability of micronizing the diclofenac particles with a slight modification in the crystalline structure and physical properties such as melting point and heat of fusion. So, this process could be used to micronize the diclofenac particles which are poorly soluble in water to enhance its solubility and better absorption in body. Acknowledgment The authors are grateful to the Shiraz University for supporting this research. References [1] M. Turk, P. Hils, B. Helfgen, K. Schaber, H.-J. Martin, M.A. Wahl, Micronization of pharmaceutical substances by the rapid expansion of supercritical solutions (RESS): a promising method to improve bioavailability of poorly soluble pharmaceutical agents, J. Supercrit. Fluids 22 (2002) 75–84.

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