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Experimental Study of Nano Particles Formation through Rapid Expansion of Supercritical CO2 Mahya Sameia, Alireza Vatanarab, Shohreh Fatemia,* a School of Chemical Engineering, University College of Engineering, Tehran University, Tehran, 11365–4563, Iran b Department of Pharmaceutics, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran * School of Chemical Engineering, University College of Engineering, Tehran University, Tehran, 11365–4563, Iran. Email: [email protected] Reducing the size of pharmaceutical particles enhances their solubility and bioavailability and therefore inhibits their side effects. An advantageous way to produce fine particles is using supercritical fluids technologies among which the rapid expansion of supercritical solutions (RESS) is of a significant importance in producing pure pharmaceuticals since no organic solvent is used. This method is limited to active substances highly soluble in supercritical fluid. Because of solubility limitations of large molecules and polar substances in supercritical CO2, rapid expansion of supercritical solutions with solid co-solvent (RESS-SC) can be used to overcome this restriction. Megestrol Acetate (MA) is a poorly water-soluble drug, used as an appetite enhancer to treat weight loss in pediatric patients with malignancies, cystic fibrosis and HIV/AIDS. In this work, submicron particles of MA were produced by RESS-SC method, using CO2 as supercritical fluid in the presence of menthol as solid co-solvent. The effect of operating conditions including extraction temperature, extraction pressure and percent of co-solvent on the average particle size of produced particles was investigated. The experiments were carried out at three temperature levels from 40 to 60 ºC, three pressure levels from 15 to 25 MPa, and with 2, to 6 percents of co-solvent. The particle size could be reduced from about 10 µm to less than 110 nm. The results showed that an increase in temperature or pressure results in smaller particles while by increasing the amount of co-solvent, larger particles were produced. 1. Introduction Controlling the size of pharmaceutical particles is an important goal in pharmaceutical industry since it increases the bioavailability of drug by improving the drug dissolution rate. Compared with conventional techniques which require numerous manufacturing steps, cause thermal and chemical degradation of products and need further purification steps, SCF-based particle formation methods produce very narrow size distribution of particles with controlled morphology in a single-step operation with mild operating temperatures. Due to its distinguishing features, CO2 is widely used as SCF. It is nontoxic, inexpensive and gaseous at ambient conditions which simplifies the problem of solvent residues. It also has mild critical conditions which minimizes thermal degradation of drugs. Among methods using SCF, rapid expansion of supercritical solutions (RESS) is the first choice since it is simpler and less expensive. This process relies on solvent properties of CO2. The active substance is dissolved in supercritical CO2 (SC-CO2) and the mixture formed is expanded in a very short time (less than 10-5 sec), causing high supersaturation ratios and formation of small particles. The main problem with RESS process is that it is not practical for substances with low solubility in SC-CO2 which is true about most polar drugs. In a modified RESS process, a cosolvent is added to provide a higher solubility at lower pressures due to specific molecular interactions (RESS-SC). Menthol is a common co-solvent which is widely used in food and pharmaceutical industry. It shows high solubility in SC-CO2, is solid at ambient conditions, does not react with SC-CO2 or solute, and is easily removed by sublimation (Kayrak et al., 2003; Fages et al., 2004; Thakur and Gupta, 2006; Pasquali and Bettini, 2008). The precipitation phenomenon in RESS process is quite complicated and many factors simultaneously affect the nucleation and growth of particles and result in particles with different sizes and shapes. Many researchers have tried to find out how operating conditions alter the final product. However, the obtained results cannot be extended to all cases and are sometimes contradictory. The main factors that should be considered in controlling the size of particles formed by RESS-SC method are pressure and temperature of extraction and expansion units, concentration of drug, amount of cosolvent, nuzzle length and diameter, spray distance and collision angle (Huang et al., 2005; Yildiz et al., 2007). The aim of this work is to study the effect of main parameters on nano particle fabrication of Megestrol Acetate (MA) which was rapidly expanded from supercritical CO2 to atmosphere. In this research the way that extraction pressure and temperature and co-solvent content affect the average particle size of outlet material is investigated. 2. Experimental CO2 was used as solvent, megestrol acetate (MA) as the model substance and menthol as solid co-solvent. A schematic of apparatus used in RESS-SC process is illustrated in figure 1. Figure 1: Schematic diagram of RESS process CO2 reached the desired temperature and pressure by passing the pump and heater, and in supercritical state, entered the extraction cell previously filled with MA and menthol in specific ratios and glass beads as packing. The mixture was left for hours to provide the time needed for MA to dissolve in SC-CO2. The exit valve was then opened to let the solution expand into atmospheric conditions through a heated nozzle, and particles precipitated on a surface perpendicular to and 10 cm from the nozzle outlet. The extraction pressure, extraction temperature and amount of co-solvent were the varying parameters with low and high levels of 15 and 25 MPa, 40 and 60 ºC, and 2 and 6% respectively. A two-level factorial design with three factors was used and the results were assessed by Design Expert software. The morphology of formed particles was characterized by scanning electron microscopy (SEM) and average particle sizes were obtained using a nanosizer device (Malvern, NANO-ZS). 3. Results and discussions The results of all 11 experiments are summarized in table 1. The average particle sizes are in range of 102.8 to 516.3 nm. Table 1: Experimental conditions and results Run 1 2 3 4 5 6 7 8 9 10 11 Temperature (ºC) 40 60 40 60 40 60 40 60 50 50 50 Pressure (MPa) 15 15 25 25 15 15 25 25 20 20 20 Co-solvent (wt%) 2 2 2 2 6 6 6 6 4 4 4 Average Size (nm) 403.5 302.6 138.1 119.2 516.3 403.2 118.2 102.8 191.9 268.2 232.6 3.1 Effect of pressure It is clear from figure 2 that in both 40 and 60 ºC smaller particles were formed at higher pressures. The same results have been reported for taxol (Yildiz et al., 2007) and sulindac (Hezave and Esmaeilzadeh, 2010), but about salicylic acid and aspirin there was an optimum pressure and increasing the pressure more than that, formed larger particles (Huang et al., 2005; Yildiz et al., 2007).The decrease in particle size with increasing pressure can be explained as follows: At constant temperature, the solubility of MA in SC-CO2 increases with pressure and so does the supersaturation, therefore nucleation rate rises and particle size is reduced. Figure 2: Average particle size of MA vs. Extraction pressure 3.2 Effect of temperature Figure 3 shows that increasing the temperature results in smaller particles. This increase is more considerable at lower pressures. An increase in temperature causes the density of SCF solvent to fall and decreases the solubility. On the other hand, the volatility of the substance increases as the temperature rises and leads to a higher solubility (Mukhopadhyay, 2000). The existing data (dean et al.,1995) indicate that in pressures from 80 to 22.5 MPa, MA becomes more soluble in CO2 at higher temperatures. A greater solubility means larger supersaturation and smaller particles as was observed in our experiments. This is similar to what is reported for lidocaine (Kim et al., 2010). It has been reported that for salicylic acid (Yildiz et al., 2007) and aspirin (Huang et al., 2005), up to a point increasing the temperature led to smaller particles but further increase of temperature showed the opposite effect and resulted in larger particles. Figure 3: Average particle size of MA vs. Extraction temperature 3.3 Effect of co-solvent As indicated in figure 4, co-solvent has different effects at different pressures. At 25 MPa adding co-solvent has a positive effect on particle size while at 15 MPa adding more co-solvent leads to larger particles. The amount and nature of co-solvent affects the degree to which the polarity of supercritical fluid phase is modified. Here at 15 MPa, more MA is dissolved in SC-CO2 by adding more co-solvent. Particle collision rate is directly proportional to the square of particle concentration, so this higher concentration of MA caused by menthol means more coagulation and larger particles. Figure 4: Average particle size of MA vs. Percent of co-solvent Another effect of adding co-solvent is hindering particle growth in expansion zone by surrounding the drug and preventing surface to surface interaction between drug particles. This effect causes getting smaller particles by more amount of co-solvent at 25 MPa. 3.4 SEM results Among three factors discussed above, Pressure has the greatest effect. All experiments done at the highest pressure (25 MPa) resulted in smallest particles and their size differences are not considerable in nano scale. SEM images of run 4 are presented in figure 5. Figure 5: SEM images of run 4 Figure 5 shows that very fine particles formed primarily, are agglomerated. It can be referred to menthol as solid co-solvent, which is left inside droplets in the very short time CO2 changes to gas. Some spherical larger particles are also formed as can be seen in figure 5. SEM images of particles in other experiments have almost the same shape, but for example in run 6, more large spherical particles were formed. 4. Conclusion In this work, MA particles were formed in nano scale through rapid expansion of supercritical CO2 and with menthol as solid co-solvent. Effect of temperature, pressure and weight percent of co-solvent on average particle size was investigated performing a 2-level full factorial design. It was found that all three parameters influence the particle size of outlet material, although it was observed that the average size of precipitated particles was most sensitive to pressure and at higher pressures, finer particles were produced. At the best conditions, the average size of MA particles could reach from nearly 10 µm to less than 120 nm. References Dean J. R., Kane M., Khundker S., Dowle C., Tranter R.L. and Jones P., 1995, Analyst 120, 2153-2157. 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