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Process intensification of anti-solvent crystallization of salicylic acid using ultrasonic irradiations
Chemical Engineering and Processing 57–58 (2012) 16–24
Contents lists available at SciVerse ScienceDirect
Chemical Engineering and Processing: Process Intensification journal homepage: www.elsevier.com/locate/cep
Process intensification of anti-solvent crystallization of salicylic acid using ultrasonic irradiations Ujwal N. Hatkar, Parag R. Gogate ∗ Department of Chemical Engineering, Institute of Chemical Technology, Matunga, Mumbai 400019, India
a r t i c l e
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Article history: Received 26 July 2011 Received in revised form 26 April 2012 Accepted 27 April 2012 Available online 5 May 2012 Keywords: Anti-solvent crystallization Sonication Average particle size Crystal characteristics Agglomeration
a b s t r a c t Anti-solvent crystallization of salicylic acid has been investigated using conventional stirring approach and under the influence of ultrasound. During silent conditions, experiments have been conducted to study the effect of various parameters such as solution concentration, standing time, solvent–anti-solvent ratio, temperature, stirring speed and solution injection rate on the crystal characteristics. It was observed that the average particle size increased with an increase in the solution concentration and solvent/antisolvent ratio while the change in temperature had marginal effect on the particle size. Ultrasound related variables such as irradiation time, moment of application, power and frequency of ultrasound and type of reactor have been varied to investigate the effect on the particle size distribution. It was observed that, the average particle size of salicylic acid crystals reduced with an increase in the irradiation time and power of ultrasound. The exact time of application of ultrasound altered the average particle size of crystals and significantly affected the agglomeration of crystals. The effect of ultrasound was more intense when horn was used for irradiation instead of ultrasonic bath. Use of ultrasonic irradiations also resulted in narrow distribution of the particles which is a distinct advantage especially considering the possible pharmaceutical applications of sonocrystallization. © 2012 Elsevier B.V. All rights reserved.
1. Introduction Crystallization is an important processing step significantly affecting the final product characteristics and generally required in all the industrial domains including fine chemical and pharmaceutical industries. Crystallization of drug molecules using anti-solvent is widely practiced in pharmaceutical industries to produce active pharmaceutical ingredients. An important advantage of the antisolvent crystallization approach is that it eliminates the use of thermal energy which can reduce the activity of the temperature sensitive materials. Thus, anti-solvent crystallization is preferred over evaporation-based crystallization which also requires expensive energy-intensive equipment. However the physicochemical properties of the anti-solvent significantly affect the rate of mixing with the solutions, and can result in abrupt change in supersaturation and ultimately alter the nucleation rate and crystal growth of the precipitating compounds. Many modern drugs are hydrophobic and have poor solubility in water. Industrially anti-solvent crystallization using water has been extensively used to precipitate such drugs. Water has many advantages as an anti-solvent but
∗ Corresponding author. Tel.: +91 22 3361 2024; fax: +91 22 3361 1020. E-mail addresses: [email protected], [email protected] (P.R. Gogate). 0255-2701/$ – see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.cep.2012.04.005
employing water results in delayed mixing rate between the solution and anti-solvent because of the low miscibility of water in organic solutions. The low rate of mixing may limit the fast local supersaturation and hence can decrease the rate of nucleation and subsequent particle formation, which can lead to the formation of large crystals with a broad crystal size distribution [1,2]. In addition, the conditions involved in crystallization experiments strongly affect the particle formation mechanism and govern the resulting particle size and its distributions. Hence controlling crystal size and distribution has been the most important concern related to antisolvent crystallization processes involving water. Use of ultrasound offers an effective variable to control anti-solvent crystallization and overcome problems related to crystal size distribution. Ultrasound assisted crystallization has been generally described as sonocrystallization. In the past few decades researchers have found that, ultrasound can be effectively used in beneficial ways to control the different stages of crystallization operation including the nucleation and growth of crystals [3–8]. Ultrasound as an energy source has been shown to be capable of inducing nucleation at lower supersaturation than conventional agitation. Use of ultrasound can also reduce the metastable zone width and induction time required for onset of crystallization [6]. Ultrasound results in rapid and uniform mixing, improves crystal form and crystal size distribution and reduces the agglomeration. By adjusting ultrasound related variables such as the power density and ultrasonic
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duration accompanied with proper crystallization conditions, the mean size and size distribution of precipitated crystals can be effectively controlled. The products formed by sonocrystallization are superior to those obtained by conventional crystallization since the crystal size distribution obtained using ultrasound is narrow and agglomeration in most of the cases is found to be reduced without altering the crystallinity of crystals, which is desired particularly in pharmaceutical industry. Ultrasound has been used to change the crystal size distribution of the anti-solvent crystallization process [7,8]. Size reduction of the high energy materials during anti-solvent crystallization by conventional methods (mechanical means) is not safe as they are very sensitive to friction and impact and in such cases sonocrystallization can be effectively used [5]. Ultrasound increased the crystal growth rate of potash alum and it was also observed that the crystals grown under ultrasound were smaller than those produced in a non-insonated, stirred crystallizer [9]. The objective of this study was to investigate the effect of various process parameters on anti-solvent crystallization under silent condition and subsequently under the influence of ultrasound to understand the effect on the crystal size distribution. In this work anti-solvent crystallization of salicylic acid has been carried out using water as anti-solvent under silent condition (without ultrasound) and under the influence of ultrasound. The studies related to salicylic acid crystallization are quite important considering the dependency of the applications on the particle size distribution and some of the early studies on spherical crystallization of salicylic acid were by the group of Kawashima [10–12]. It has been established that initial temperature of the salicylic acid plays an important role in deciding the crystal size and it was reported that with an increase in the temperature, larger agglomerates with less spherical forms composed of larger crystals were obtained. Blandin et al. [13] have also investigated the mechanistic details of precipitation of salicylic acid and reported that at low supersaturation conditions in the stirred vessel, the primary nucleation is of heterogeneous type and the secondary nucleation is dominant, whereas homogeneous primary nucleation dominates in the T-mixer at high supersaturations. Nordström and Rasmuson [14] have also investigated the polymorphism in the crystallization of salicylic acid. A careful analysis of the earlier works related to salicylic acid crystallization indicates that none of the studies were based on the use of ultrasound to alter the particle size distribution and hence the novelty of the current work is clearly established. During anti-solvent crystallization under silent conditions, parameters like solution concentration, standing time, solvent–anti-solvent ratio, temperature, stirring speed and solution injection rate were optimized with an objective of obtaining the salicylic acid crystals with narrow crystal size distribution. The optimized set of conditions were then used under the influence of ultrasound to investigate the effect of ultrasound and ultrasound related variables on the crystal size distribution using ultrasonic bath. During sonocrystallization, ultrasound related variables (time of sonication, moment of application of ultrasound, power of ultrasound, and frequency of ultrasound) were optimized. The effect of mode of irradiation (exposing the solution to ultrasonic waves) was also investigated by using an ultrasonic horn (direct irradiation by virtue of horn being dipped in the solution) to compare with the results obtained by indirect irradiation using an ultrasonic bath. The intensification aspect in the current work deals with the use of alternate source of energy in the form of ultrasound for obtaining the desired particle size distribution. In the case of pharmaceutical industry, obtaining the desired narrow particle size distribution is very important and any batches not meeting the specifications would mean additional processing. Use of ultrasound can effectively eliminate the additional processing
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as well as improve on the time of crystallization which can be considered as the intensification of the crystallization operation. 2. Experimental methods 2.1. Materials Salicylic acid (C7 H6 O3 ) was purchased from SD fine chemicals Ltd., India. Solvent used was ethanol (99.9%), due to its high miscibility with water and was, also purchased from SD fine chemicals Ltd., India. Distilled water was used as anti-solvent, which has been prepared in laboratory by all glass distilled water unit procured from Borosil Glass Ltd., India. 2.2. Apparatus and experimental procedure Fig. 1 shows the schematic of experimental apparatus used for anti-solvent crystallization of salicylic acid under silent conditions (without ultrasound). The main purpose of using agitation was to rapidly mix the solution of salicylic acid in ethanol with anti-solvent water. The apparatus consists of a two neck flat bottom cylindrical glass reactor with a capacity of 0.15 L. The reactor was a cylindrical vessel with a diameter of 0.05 m and maximum height of 0.10 m but the maximum liquid height was always restricted to 0.075 m for operational ease. A burette was placed just above the small neck of reactor supported by the metal stand, to add the solution of salicylic acid in ethanol into the reactor. A pitched-blade metal disk turbine (diameter of 0.03 m) rotated by an electric motor was inserted through the bigger neck as shown in the schematic, to agitate the solution in the reactor. The clearance of the agitator from the bottom of the reactor was 0.005 m. A constant temperature bath was assembled with the apparatus to maintain the temperature. In case of experiments involving ultrasonic bath (procured from Dakshin, Mumbai with a power range of 100–200 W and frequency of 40 kHz and 25 kHz), the two neck flat bottom cylindrical reactor was placed in ultrasonic bath which produces the ultrasonic waves irradiating the solution in reactor indirectly. The power of ultrasound is adjustable and can be varied from 100 to 200 W. The available
Fig. 1. Experimental apparatus used for silent condition: (A) two neck flat bottom cylindrical glass reactor, (B) pitched-blade disk turbine, (C) burette, (D) metal stand, and (E) constant temperature bath.
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generator is a dual frequency generator which can generate waves of 25 kHz and 40 kHz frequencies. In case of sonocrystallization using ultrasonic horn, the only change in apparatus as compared to apparatus used for conventional crystallization was that the stirrer was replaced by ultrasonic horn also procured from Dakshin, Mumbai. The generator can generate the ultrasonic waves of 40 kHz frequency and the power of horn was fixed at 138 W. The sonocrystallization using horn is different than using ultrasonic bath assembly, as in former case the irradiation are directly passed into the solution in reactor by directly immersing the tip of the horn in the solution, whereas in the case of ultrasonic bath, the transducers attached at the bottom of bath are not in contact with the solution. Indirect irradiation is preferred in case where metal contamination is strictly avoided especially in the case of pharmaceutical drugs. For the anti-solvent crystallization of salicylic acid under silent condition experiments were carried to study the effect of solution concentration at 0.1, 0.15 and 0.2 kg/L of salicylic acid in ethanol. First, the distilled water (quantity depends on solvent–anti-solvent ratio) was taken in reactor and bath temperature was maintained as desired. The water was agitated using the pitched-blade disk turbine for a while in order to ensure that the water should attain the bath temperature. Exactly 0.02 L solution (salicylic acid dissolved in ethanol) was then taken in burette and was added to anti-solvent drop wise until it was finished completely. The exact position of the injection was inside the liquid midpoint between the agitator position at the center (ultrasonic horn in the case of experiments with ultrasonic horn) and the wall of the reactor. As soon as the solution was added to water the solute experienced the supersaturation. The mixing with anti-solvent decreased the solubility of salicylic acid in ethanol and ultimately resulted in prompt precipitation. The solution was then allowed to stand for different time span ranged between 1 and 12 h to complete crystal growth. To study the effect of temperature on crystallization the bath temperature was varied from 25 to 35 ◦ C (total of 3 different operating temperatures). Experiments were also carried out in order to study the effect of solvent–anti-solvent ratio (1:2 and 1:3). The operating stirring speed was varied between 320 and 600 rpm in order to investigate the effect of degree of mixing. Apart from drop wise addition (0.2 mL/s); the solution was released into the anti-solvent at three different injection rates of 2, 4 and 6 mL/s, to study the effect of solution injection rate. A peristaltic pump (procured from Enertech, India) was used to vary the solution injection rate. These experiments were repeated under silent condition and under the influence of ultrasonic wave. The ultrasound was applied to the system during the solution injection and crystal growth stages. The crystallizing chamber was sonicated using an ultrasonic bath and an immersed probe described earlier. In the case of sonocrystallization, ultrasonic power output, irradiation time, and the moment of application of ultrasound were varied. Apart from these three variables, effect of frequency of ultrasound was also studied using ultrasonic bath at two different frequencies of 25 kHz and 40 kHz respectively. The obtained crystals from the conventional and ultrasound assisted crystallization processes were filtered using vacuum and dried in oven. At the scales of operation used in the present work, not much problems were encountered for the separation of crystals using filtration. The dried crystals were photographed using 10× optical zoom microscope for crystal shape and size analysis. The dimensions of the photographs and the resolutions were adjusted in such a way that sufficient clarity was obtained for exact analysis of the size of the crystals. Also number of photographs have been considered to check the reproducibility of the obtained data for the crystal size. The exact size as described in the work refers to the maximum dimension of the needle shaped crystals of salicylic acid. For obtaining the crystal size distribution, known amount of
dried crystals were photographed and analyzed using ImageJ software for size distribution. Again repetitive analysis has been done to get reproducible results for the size distribution and the mean size reported in the work. 3. Results and discussion 3.1. Effect of various parameters under silent conditions Experiments were carried out under silent conditions to study the effect of various parameters including solution concentration, standing time, solvent–anti-solvent ratio, temperature, stirring speed and solution injection rate. The aim of these experiments was to obtain a set of operating conditions which will produce crystals with improved form and lower average particle size with relatively narrow crystal size distribution. 3.1.1. Effect of standing time Experiments were carried out to study the effect of standing time described as the time for which the solution was kept agitated after the complete addition of solution from burette in the reactor. Effect of standing time was investigated by allowing the solution to stand for different time intervals such as 1, 2, 4, 8 and 12 h respectively. The solution concentration, solvent–anti-solvent ratio, temperature, stirring speed, solution injection rate were fixed at 0.1 kg/L, 1:2, 30 ◦ C, 320 rpm and 0.2 mL/s respectively. It was observed that the average particle size of salicylic acid crystals obtained was almost constant at around 320 m for different standing times. It indicates that the particle size was unaffected even if solution was allowed to stand for very long duration. Examination under microscope also revealed that the crystal form remains same during all experiments. Thus from these results; effective time of standing can be finalized as 1 h for further optimization experiments, concluding that it is sufficient for complete crystal growth. 3.1.2. Effect of solution concentration The effect of concentration of solution was investigated using three different concentrations. Solutions with 0.1, 0.15 and 0.2 kg/L concentrations were injected into the anti-solvent through burette at 0.2 mL/s. The stirring speed was kept fixed at 320 rpm. However temperature and solvent–anti-solvent ratio were also varied in order to study the effect of solution concentration at different temperature and solvent–anti-solvent ratio. The temperatures were 25 and 30 ◦ C while the different solvent–anti-solvent ratios used were 1:2 and 1:3 respectively. The solution was allowed to stand for 1 h for crystal growth. Fig. 2 shows the effect of solution concentration at two different temperatures. According to the figure, the average particle size of salicylic acid decreases with an increase in the solution concentration. However the effect is more at higher temperature. It can be seen that the reduction in average particle size is more at 30 ◦ C as compared to 25 ◦ C. These results can be justified by the dependency of nucleation process on solution concentration and temperature. Higher concentrations of solution should produce a higher degree of supersaturation upon the mixing with the antisolvent, and as a result, rate of nucleation increases. The high rate of nucleation represents the formation of a large number of nuclei per unit time and leads to an increase in the number of crystals. This could make the size of each crystal smaller resulting in a decrease in the average particle size [15]. Also, the nucleation rate increases with increase in temperature [16]. Hence at higher temperature the nucleation rates are higher which results in a decrease in particle size as explained earlier. Thus the combination of high concentration with high temperature results in more reduction in particle size than with relatively low temperature. As shown in Fig. 3, it was
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Table 1 Effect of solution injection rate on average particle size of salicylic acid crystals experiments were conducted at 30 ◦ C, with solution concentration of 0.1 g/mL, stirring speed of 320 rpm and solvent–anti-solvent ratio of 1:2. Solution injection rate (mL/s)
Average particle size (m)
0.2 2 4 6
320 390 392 394
process would indeed be dependent on the degree of temperature adjustments required in the process.
Fig. 2. Average particle size of salicylic acid crystals as a function of solution concentrations at different temperatures and 1:2 solvent–anti-solvent ratio, experiments were conducted at 320 rpm and solution injection rate of 0.2 mL/s. 25 ◦ C, 30 ◦ C.
found that the solution concentration has no effect on crystal form till the concentration of solution was 0.15 kg/L. It was observed that at 0.2 kg/L the obtained crystals were found with somewhat reduced width as compared to crystals obtained at 0.1 kg/L. 3.1.3. Effect of temperature The effect of temperature on crystal form and average particle size was investigated in the range of 25–35 ◦ C; at solution concentration of 0.1 kg/L, stirring speed of 320 rpm and solution injection rate of 0.2 mL/s respectively. The standing time allowed for crystal growth was 1 h and solvent–anti-solvent ratio used was 1:2. It was found that the temperature had no effect on crystal form and average particle size. The average particle size was 320 m at 25 ◦ C, 318 m at 30 ◦ C, and 316 m at 35 ◦ C respectively. However according to the theory of nucleation the nucleation rate is directly proportional to temperature. Effect of temperature on nucleation kinetics of ␣ l-glutamic acid was investigated in the range of 25–45 ◦ C and according to the results obtained, the nucleation rate was found to be increased with temperature [3]. Thus at higher temperature the average particle size of obtained salicylic acid crystals should reduce, but it was not the case in the present work as the average particle size is almost unaffected by increase in temperature. The reason for this is relatively small increment in operating temperature which was unable to alter the supersaturation significantly. As the effect of temperature on the particle size was not so significant, the further experiments have been performed at 30 ◦ C operating temperature as it was found to be matching with the ambient conditions and hence incorporated minimal load on the cooling or heating characteristics. The overall economics of the
3.1.4. Effect of solvent/anti-solvent ratio Solvent/anti-solvent ratio governs the supersaturation and hence the effect of solvent–anti-solvent ratio on crystal form and average particle size was investigated using two different solvent/anti-solvent ratios; 1:2 and 1:3 respectively. Other parameters like solution concentration, temperature, stirring speed, solution injection rate were fixed at 0.15 kg/L, 30 ◦ C, 320 rpm and 0.2 mL/s respectively. The standing time allowed for crystal growth was fixed at 1 h. It was observed that the crystal form remains unchanged even if the ratio was varied but the average particle size was significantly affected. The average particle size of salicylic acid crystals at 1:2 solvent–anti-solvent ratio was 260 m while the crystals obtained at 1:3 solvent–anti-solvent ratio had average particle size of 224 m. It indicates that the average particle was reduced as the solvent–anti-solvent ratio was increased. The reason for the reduction is increase in nucleation rate. Supersaturation is increased as a result of increment in ratio, since anti-solvent volume added goes up which leads to higher nucleation rate resulting in decrease in average particle size. 3.1.5. Effect of solution injection rate The effect of solution injection rate was investigated in the operating range of 0.2–6 mL/s. Other parameters like solution concentration, temperature, stirring speed, solvent–anti-solvent ratio were fixed at 0.1 kg/L, 30 ◦ C, 320 rpm and 1:2 respectively. The standing time allowed for crystal growth was 1 h. Interestingly it was found that the solution injection rate not only affects the average particle size but also the crystal form was altered. Table 1 represents the obtained average particle size for various solution injection rates. It can be observed from table that the increase in solution injection rate has increased the average particle size of salicylic acid crystals. However the increase in solution injection rate beyond 2 mL/s had no effect on average particle size of crystals. Fig. 4 shows the crystal form at different solution injection rate. The agglomeration was found to be significantly reduced at higher
Fig. 3. Effect of solution concentration on crystal form of salicylic acid; experiments were conducted at 30 ◦ C and, solvent–anti-solvent ratio of 1:2, stirring speed of 320 rpm and solution injection rate of 0.2 mL/s (a) at 0.1 g/mL, (b) at 0.15 g/mL, and (c) at 0.2 g/mL.
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Fig. 4. Effect of solution injection rate on crystal form of salicylic acid crystals, operating temperature of 30 ◦ C with solution concentration of 0.1 g/mL, stirring speed of 320 rpm and solvent–anti-solvent ratio of 1:2 (a) at 0.2 mL/s, (b) at 2 mL/s, (c) at 4 mL/s, and (d) at 6 mL/s.
injection rate and the rod shape habit of crystals was modified to needle shape habit. Study of transformation of thiazole derivative polymorphs revealed that, the addition rate of water added as antisolvent; to precipitate the thiazole derivative from methanol has found to be significantly affecting transformation at higher drug solution concentration [8]. In contrast to results obtained in this case, the increase in injection rate of drug solution has resulted in the reduction of particle size of roxithromycin crystals, when precipitated from solution in acetone using water as anti-solvent [7]. 3.1.6. Effect of stirring speed Effect of stirring speed on crystal form and average particle size was investigated in the range of 320–600 rpm; at solution concentration, temperature, solution injection rate of 0.1 kg/L, 30 ◦ C and 0.2 mL/s respectively. The standing time allowed for crystal growth was 1 h and solvent–anti-solvent ratio used was 1:2. The average particle size of salicylic acid crystals significantly decreased with an increase in stirring speed while the crystal form remained unaffected. The abrasion caused by the blades of pitched blade stirrer used for agitation increased as the rotation speed goes up resulting in decrease in average particle size. Enhanced agitation also ensured better mixing of solvent and anti-solvent. The average particle size of salicylic acid crystals obtained at 320 rpm was
320 m, at 500 rpm was 265 m and at 600 rpm the obtained size was 228 m. Increasing the speed of rotation beyond 600 rpm was not feasible in the present setup as it leads to splashing of the liquid onto the reactor walls giving problems in the overall crystallization operation and possibly errors in the measurements. Also, due to uneven distribution of the energy dissipations in the case of stirred reactor, it is expected that the quantum of fine particles generated will be higher leading to enhanced problems in filtration. Thus, in general, it might not be advisable to use very high speeds for crystallization operations. A brief analysis also indicated that when experiments were carried out with 0.1 kg/L solution concentration, 30 ◦ C operating temperature, 1:2 solvent anti-solvent ratio, 320 rpm as the speed of rotation and the solution injection rate of 2 mL/s, larger and uniform crystals were obtained when the solution was allowed to stand for one hour after its addition to anti-solvent. However the average particle size obtained was too large (390 m). This might cause the problems in downstream processing and also in terms of the final product characteristics mainly due to their needle shape and large particle size. It has also been observed that the degree of mixing and turbulence also decides the final mean crystal size and distribution. With an objective of obtaining lower mean size of crystals, experiments have been carried out using ultrasonic irradiation.
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3.2. Effect of ultrasound Ultrasonic bath and horn were used to investigate the effect of ultrasound on anti-solvent crystallization of salicylic acid. Initially experiments were targeted at investigating whether ultrasound application results in variation in the induction time for crystallization. 3.2.1. Conductivity study and effect of ultrasound on onset of crystallization Conductivity was monitored using a conductivity probe with digital display, and was recorded with respect to time to investigate the effect of ultrasound on onset of crystallization. The experiments were carried out using ultrasonic bath with 0.1 kg/L solution concentration, 30 ◦ C operating temperature, solvent–anti-solvent ratio of 1:2, 320 as speed of rotation and the anti-solvent injection rate of 0.2 mL/s. The reactor was placed in bath and initially solution was added to the reactor instead of anti-solvent (as in previous experiments). The anti-solvent was taken in burette and added to solution drop wise. The solution was irradiated with ultrasonic waves of 40 kHz for about two minutes from the addition of first drop of anti-solvent in the reactor. The conductivity probe was inserted to record the conductivity with respect to time. The experiments were repeated in the same manner but under silent condition. Fig. 5 shows the conductivity as a function of time under silent condition and under the influence of ultrasound. In both conditions initially the conductivity increased from initial value of 1.17 mmho and reached to a particular maximum value beyond which the conductivity decreased indicating onset of crystallization. The time taken to reach the limiting value of 2 mmho was 100 s under the influence of ultrasound whereas under silent condition was 140 s to reach the maximum value of 1.95 mmho. The results obtained revealed that the ultrasound brought the onset of crystallization at lower supersaturation [17–19]. The attributed mechanism was the enhanced micromixing which plays a major role in deciding the crystal quality which is very important in the case of pharmaceutical products. Also ultrasound can induce primary nucleation in nominally particle-free solutions and, noteworthy, at much lower supersaturation levels as compared to the conventional mechanical agitation based crystallization operation. Hem [20] have discussed in detail the possible reasons behind the improvement in crystallization using ultrasound including various theoretical explanations involving the action of inertial cavitation bubbles, cooling effect, pressure effect, segregation effect, and
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evaporation effect. All these effects sound reasonable and may in fact act in a complementary fashion to enhance the levels of supersaturation. Wohlgemuth et al. [21] investigated the mechanism details by replacing cavitation bubbles by gas bubbles to check if the bubble surface itself acts as nucleation center and found that process was influenced not only due to gassing, but also ultrasound effects played a major role in deciding the crystallization efficiency. Other possible reasons are cooling and evaporation effect due to the cavitational bubble generation. During cavitation bubble formation latent heat for evaporation is taken from surrounding liquid resulting in localized cooling which increases the supersaturation level. Also some quantum of liquid solvent is vaporized during the bubble formation, so that the concentration of solvent decreases locally. One more hypothesis governing the effects of ultrasound is based on the observation that the growth rate of a crystal in an ultrasonic field increases with the intensity of the ultrasound. 3.2.2. Effect of irradiation time Experiments for variation in sonication time were conducted with 0.1 g/mL solution concentration, 30 ◦ C operating temperature, 1:2 solvent–anti-solvent ratio, 320 rpm as the speed of rotation and the solution injection rate of 2 mL/s. Ultrasonic bath was used to irradiate the solution in the reactor. Ultrasound was applied as soon as the addition of solution to anti-solvent was started. Ultrasonic power used was 200 W and the frequency of ultrasound was 40 kHz. The duration of application of ultrasound was varied in the range from 1 to 10 min. Fig. 6 shows the effect of ultrasound on the crystal form. It was found that as the duration of ultrasound application was increased the average particle size significantly decreased, as shown in Table 2. The effect of power ultrasound was intense when it was applied for 3 min. The average particle size was reduced to 82 m under the influence of ultrasound from 392 m, which was obtained under silent condition. Similar effects of decrease in the particle size with the application of ultrasound as reported by many researchers [4–6]. Abbas et al. [22] have reported that the application of ultrasound to a crystallization process significantly reduced size of NaCl crystals and narrowed the size distribution. By varying temperature and sonication power output, the desired particle size (5 m) could be achieved [22]. As ultrasound was effective in decreasing the particle size significantly, it is important to give some idea about the relative power consumption in the case of ultrasonic horn as well as the silent conditions (power dissipation would be in the form of stirring). The actual power dissipation (based on the calorimetric investigations) in the case of ultrasonic bath was about 135 W/L whereas in the case of mechanical stirring the power dissipation into the liquid was around 1 W/L. Thus it appears that the power consumption in the case of ultrasonic reactors is substantially higher but in the case of pharmaceutical products the desired size distribution is very important which prompts towards the effective use of ultrasonic reactors even at commercial scale. Another distinct advantage of using ultrasound would be in terms of the fact that ultrasound can induce primary nucleation in Table 2 Effect of time of sonication of average particle size of salicylic acid experiments were conducted with 0.1 g/mL solution concentration, 30 ◦ C operating temperature, 1:2 solvent–anti-solvent ratio, 320 rpm as the speed of rotation and the solution injection rate of 2 mL/s with ultrasound at 200 W and 40 kHz.
Fig. 5. Effect of ultrasound on onset of crystallization, experiments were conducted at 0.1 g/mL solution concentration, 30 ◦ C operating temperature, solvent–antisolvent ratio of 1:2, 320 as speed of rotation and the anti-solvent injection rate of 0.2 mL/s. without ultrasound, with ultrasound.
Sonication time (min)
Average particle size (m)
0 1 2 3 5 10
392 252 140 82 54 50
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Fig. 6. Effect of ultrasound on the crystal form of salicylic acid, experiments were conducted with 0.1 g/mL solution concentration, 30 ◦ C operating temperature, 1:2 solvent–anti-solvent ratio, 320 rpm as the speed of rotation and the solution injection rate of 2 mL/s. (a) Without ultrasound and (b) with ultrasound at 200 W and 40 kHz when applied for 3 min.
nominally particle-free solutions and, noteworthy, at much lower supersaturation levels as compared to the conventional mechanical agitation based crystallization operation. The scale up of the ultrasonic reactors would be based in terms of using flow reactors (power dissipation per unit volume is expected to be lower) with multiple transducers attached to the reactor wall through which the solution will be flowing [23]. The design of systems with large numbers of transducers can give an acoustic pattern that is uniform and noncoherent above the cavitational threshold throughout the reactor working volume. The use of low-output transducers gives the additional advantage of avoiding the phenomenon of cavitational blocking (acoustic decoupling), which arises where power densities close to the delivery point are very high. In addition, these multi-transducer units very effectively concentrate ultrasonic intensity towards the central axis of the cylinder and away from the vessel walls, thus reducing problems of wall erosion and particle shedding. The vessel can be operated in batch mode or, for larger-scale work, in continuous mode whereby units can be combined in a modular fashion for “scale-out” and increased residence time. In summary, a plurality of low electrical and acoustic power (1–3 W/cm2 ) transducers produces 25–150 W/L, but ideally 40–80 W/L [23].
3.2.3. Effect of time of application of ultrasound Effect of time of ultrasound application has been investigated by applying ultrasound at different time since the moment of addition of solution to previously agitated solution, which is recorded as zero time. It was applied after various times from reference point for exactly 3 min with 0.1 kg/L solution concentration, 30 ◦ C operating temperature, 1:2 solvent–anti-solvent ratio, 320 rpm as the speed of rotation and the solution injection rate of 2 mL/s. It was found that the agglomeration is reduced only if the ultrasound was applied within 2 min from the addition of solution. If the application of ultrasound was started after more than 2 min from the moment when the addition of solution was started, obtained crystals were agglomerated and large in size. Fig. 7 shows the effect of moment of application of ultrasound on crystal form of salicylic acid. Park and Yeo [7] have also reported that the ultrasonic waves induced the reduction of particle size of roxithromycin only when it was applied to the solution at the initial stage of anti-solvent crystallization. In the case of anti-solvent crystallization, the initial mixing and the levels of supersaturation is very important and hence ultrasound must be introduced right at the point of the addition of the antisolvent to the system.
3.2.4. Effect of power of ultrasound Ultrasonic bath at 40 kHz was used to study the effect of power of ultrasound in the operating range of 100–200 W. The ultrasound was applied for 2 min from the moment of addition of solution. Experiments were conducted with 0.1 kg/L solution concentration, 30 ◦ C operating temperature, 1:2 solvent–anti-solvent ratio, 320 rpm as the speed of rotation and the solution injection rate of 2 mL/s. Table 3 shows the effect of power of ultrasound on average particle size. Abrasive effect of ultrasound was found to be more intense at higher power and the average particle size of salicylic acid crystals decreased significantly with an increase in power of ultrasound. It was reported by several researchers that increase in power of ultrasound has resulted in decreasing the particle size owing to the large effect at high power [5–7]. An increase in the power of ultrasound means that more number of cavitational events occur in the system with an enhanced degree of acoustic streaming [24–26] leading to an increase in the physical effects which control the crystallization operation in terms of avoiding agglomeration and also particle breakage. 3.2.5. Effect of frequency of ultrasound Effect of frequency of ultrasound was investigated using two different frequencies, 25 kHz and 40 kHz respectively. Ultrasonic bath at 200 W was used for sonication and ultrasound was applied for 2 min. Experiments were conducted with 0.15 kg/L solution concentration, 30 ◦ C operating temperature, 1:2 solvent–anti-solvent ratio, 320 rpm as the speed of rotation and the solution injection rate of 2 mL/s. The average particle size obtained under above conditions at 40 kHz was 259 m while an average particle size of 257 m was obtained at 25 kHz. It was found that the crystal form and crystal size was not affected by change in frequency [4]. The obtained results can be attributed to the fact that at both 25 kHz and 40 kHz operating frequencies, it is expected that the physical effects of cavitation events such as acoustic streaming accompanied with Table 3 Effect of power of ultrasound on average particle size, Experiments were conducted at 40 kHz and 2 min of sonication time with 0.1 g/mL solution concentration, 30 ◦ C operating temperature, 1:2 solvent–anti-solvent ratio, 320 rpm as the speed of rotation and the solution injection rate of 2 mL/s. Power of ultrasound (W)
Average particle size (m)
0 120 154 200
390 260 205 140
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Fig. 7. Effect of moment of application of ultrasound, with 0.1 g/mL solution concentration, 30 ◦ C operating temperature, 1:2 solvent–anti-solvent ratio, 320 rpm as the speed of rotation and the solution injection rate of 2 mL/s. (a) Ultrasound was applied as soon as the solution addition started and (b) ultrasound was applied after 4 min from the moment when addition of solution was started.
turbulence is dominant whereas the chemical effects will be dominant at much higher frequencies of irradiation (above 200 kHz). 3.2.6. Effect of direct irradiation (sonocrystallization using horn) Experiments were conducted to compare the effects of direct and indirect ultrasonic irradiation. Direct irradiation experiments were conducted using 40 kHz ultrasonic horn at 138 W, the tip of horn is directly immersed in anti-solvent, with 0.1 kg/L solution concentration, 30 ◦ C operating temperature, 1:2 solvent–antisolvent ratio, 320 rpm as the speed of rotation and the solution injection rate of 2 mL/s. The ultrasound was applied for 2 min and after that the solution was kept agitated by magnetic stirrer at moderate speed. It was observed that the effect of ultrasound is more when horn was used for irradiation instead of bath. The average particle size of crystal obtained was 146 m at 138 W while average particle size of 205 m was obtained with bath when the power of ultrasound was 154 W. It appears that use of ultrasonic horn gives better results at equivalent levels of power dissipation but the possibility of contamination due to the erosion of the horn tip needs to be explored before selecting the final mode of operation. In the case of pharmaceutical applications, any type of contamination must be strictly avoided and hence designs for scale up will be based on the flow cell type of configuration with transducers attached to the wall of the reactor. 4. Conclusions The present work have shown that various parameters like solution concentration, standing time, solvent–anti-solvent ratio, temperature, stirring speed and solution injection rate significantly affects the anti-solvent crystallization of salicylic acid from ethanol using water. The average particle size was found to decrease with an increase in solution concentration, stirring speed and solvent–anti-solvent ratio. The effect of temperature at solution concentration of 0.1 kg/L on average particle size was negligible. Increase in solution injection rate resulted in reduction in agglomeration and rod shape crystals turned into needle like structures. Optimization of the different variables gave the best set of conditions as 0.1 kg/L solution concentration, 30 ◦ C operating temperature, 1:2 solvent–anti-solvent ratio, 320 rpm as the speed of rotation and the solution injection rate of 2 mL/s. When antisolvent crystallization of salicylic acid was carried out using these conditions and allowing a standing time of 1 h, the obtained crystals were more uniform and crystal size distribution was improved. It has been clearly established that ultrasound can be effectively used to control the anti-solvent crystallization process in terms of the mean size of obtained crystals and its distribution. During
sonocrystallization experiments, ultrasound related variables like irradiation time, power of ultrasound, moment of application of ultrasound have been found to affect the crystal size distribution whereas frequency did not have much effect over the range of frequencies investigated in the present work. It was found that irradiation time and power of ultrasound decreased the average particle size. The moment of application of ultrasound is critical and it should be applied at the initial stage of crystallization. Experiments at 200 W using ultrasonic bath, applying ultrasound as soon as the addition of solution started for 2 min with ultrasound frequency of 25 kHz or 40 kHz, resulted in small crystal size and agglomeration was significantly reduced. The effect of ultrasound is more if the horn is used instead of ultrasonic bath though the possibility of the contamination needs to be explored. The power consumption in the case of ultrasound reactors appeared to be higher as compared to the stirred reactor but the main advantage will be in terms of improvement in the crystallization process which can lead to higher rates of processing with minimal rejection of the batches. Also, better particle size distribution will mean that rapid filtration can be obtained as the crystals of a more uniform size and compact habit can be filtered much more rapidly.
References [1] Z. Guo, M. Zhang, H. Li, J. Wang, E. Kougoulos, Effect of ultrasound on antisolvent crystallization process, Journal of Crystal Growth 273 (2005) 555. [2] B.K. Park, S.H. Jeong, D.J. Kim, J.H. Moon, Synthesis and size control of mono disperse copper nano particles by polyol method, Journal of Colloid and Interface Science 311 (2007) 417. [3] C. Lindenberg, M. Mazzotti, Effect of temperature on the nucleation kinetics of an l-glutamic acid, Journal of Crystal Growth 311 (2009) 1178. [4] H. Li, J. Wang, Y. Bao, Z. Guo, M. Zhang, Rapid crystallization in salting out process, Journal of Crystal Growth 247 (2003) 192. [5] M.N. Patil, G.M. Gore, A.B. Pandit, Ultrasonically controlled particle size distribution of explosives: a safe method, Ultrasonics Sonochemistry 15 (2008) 177. [6] M.D. Luque de Castro, F. Priego-Capote, Ultrasound-assisted crystallization, Ultrasonics Sonochemistry 14 (2007) 717. [7] M. Park, S. Yeo, Anti-solvent crystallization of roxithromycin and the effect of ultrasound, Separation Science and Technology 45 (2010) 1402. [8] M. Kitamura, M. Sugimoto, Anti-solvent crystallization and transformation of thiazolederivative polymorphs. I: effect of addition rate and initial concentrations, Journal of Crystal Growth 257 (2003) 177. [9] N. Amara, B. Ratsimba, A.M. Wilhelm, H. Delmas, Growth rate of potash alum crystals: comparison of silent and ultrasonic conditions, Ultrasonics Sonochemistry 11 (2004) 17. [10] Y. Kawashima, M. Okumura, H. Takenaka, The effects of temperature on the spherical crystallization of salicylic acid, Powder Technology 39 (1984) 41. [11] Y. Kawashima, M. Okumura, H. Takenaka, Spherical crystallization: direct spherical agglomeration of salicylic acid crystals during crystallization, Science 216 (1982) 1127. [12] Y. Kawashima, M. Okumura, H. Takenaka, A. Kojima, Direct preparation of spherically agglomerated salicylic acid crystals during crystallization, Journal of Pharmaceutical Sciences 73 (1984) 1535.
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[13] A.F. Blandin, D. Mangin, V. Nallet, J.P. Klein, J.M. Bossoutrot, Kinetics identification of salicylic acid precipitation through experiments in a batch stirred vessel and a T-mixer, Chemical Engineering Journal 81 (2001) 91. [14] F.L. Nordström, A.C. Rasmuson, Polymorphism and thermodynamics of mhydroxybenzoic acid, European Journal of Pharmaceutical Sciences 28 (2006) 377. [15] R.K. Bund, A.B. Pandit, Sonocrystallization: effect on lactose recovery and crystal habit, Ultrasonics Sonochemistry 14 (2007) 143. [16] J.W. Mullin, Crystallization, Butterworth & Co., London, UK, 1971. [17] N. Lyczko, F. Espitalier, O. Louisnard, J. Schwartzentruber, Effect of ultrasound on the induction time and the metastable zone widths of potassium sulphate, Chemical Engineering Journal 86 (2002) 233. [18] N. Amara, B. Ratsimba, A.M. Wilhelm, H. Delmas, Crystallization of potash alum: effect of power ultrasound, Ultrasonics Sonochemistry 8 (2001) 265. [19] S.J. Park, S.D. Yeo, Recrystallization of caffeine using gas anti-solvent process, Journal of Supercritical Fluids 47 (2008) 85. [20] S.L. Hem, The effect of ultrasonic vibrations on crystallization processes, Ultrasonics (1967) 202.
[21] K. Wohlgemuth, A. Kordylla, F. Ruether, G. Schembecker, Experimental study of the effect of bubbles on nucleation during batch cooling crystallization, Chemical Engineering Science 64 (2009) 4155. [22] A. Abbas, M. Srour, P. Tangc, H. Tangc, H. Chan, J.A. Romagnoli, Sonocrystallisation of sodium chloride particles for inhalation, Chemical Engineering Science 62 (2007) 2445. [23] G. Ruecroft, D. Hipkiss, T. Ly, N. Maxted, P.W. Cains, Sonocrystallization: the use of ultrasound for improved industrial crystallization, Organic Process Research and Development 9 (2005) 923. [24] P.R. Gogate, A.B. Pandit, Sonochemical reactors: scale up aspects, Ultrasonics Sonochemistry 11 (2004) 105. [25] V.S. Sutkar, P.R. Gogate, Design aspects of sonochemical reactors: techniques for understanding cavitational activity distribution and effect of operating parameters, Chemical Engineering Journal 155 (2009) 26. [26] Ajay Kumar, P.R. Gogate, A.B. Pandit, H. Delmas, A.M. Wilhelm, Gas liquid mass transfer studies in sonochemical reactors, Industrial and Engineering Chemistry Research 43 (2004) 1812.
Contents lists available at SciVerse ScienceDirect
Chemical Engineering and Processing: Process Intensification journal homepage: www.elsevier.com/locate/cep
Process intensification of anti-solvent crystallization of salicylic acid using ultrasonic irradiations Ujwal N. Hatkar, Parag R. Gogate ∗ Department of Chemical Engineering, Institute of Chemical Technology, Matunga, Mumbai 400019, India
a r t i c l e
i n f o
Article history: Received 26 July 2011 Received in revised form 26 April 2012 Accepted 27 April 2012 Available online 5 May 2012 Keywords: Anti-solvent crystallization Sonication Average particle size Crystal characteristics Agglomeration
a b s t r a c t Anti-solvent crystallization of salicylic acid has been investigated using conventional stirring approach and under the influence of ultrasound. During silent conditions, experiments have been conducted to study the effect of various parameters such as solution concentration, standing time, solvent–anti-solvent ratio, temperature, stirring speed and solution injection rate on the crystal characteristics. It was observed that the average particle size increased with an increase in the solution concentration and solvent/antisolvent ratio while the change in temperature had marginal effect on the particle size. Ultrasound related variables such as irradiation time, moment of application, power and frequency of ultrasound and type of reactor have been varied to investigate the effect on the particle size distribution. It was observed that, the average particle size of salicylic acid crystals reduced with an increase in the irradiation time and power of ultrasound. The exact time of application of ultrasound altered the average particle size of crystals and significantly affected the agglomeration of crystals. The effect of ultrasound was more intense when horn was used for irradiation instead of ultrasonic bath. Use of ultrasonic irradiations also resulted in narrow distribution of the particles which is a distinct advantage especially considering the possible pharmaceutical applications of sonocrystallization. © 2012 Elsevier B.V. All rights reserved.
1. Introduction Crystallization is an important processing step significantly affecting the final product characteristics and generally required in all the industrial domains including fine chemical and pharmaceutical industries. Crystallization of drug molecules using anti-solvent is widely practiced in pharmaceutical industries to produce active pharmaceutical ingredients. An important advantage of the antisolvent crystallization approach is that it eliminates the use of thermal energy which can reduce the activity of the temperature sensitive materials. Thus, anti-solvent crystallization is preferred over evaporation-based crystallization which also requires expensive energy-intensive equipment. However the physicochemical properties of the anti-solvent significantly affect the rate of mixing with the solutions, and can result in abrupt change in supersaturation and ultimately alter the nucleation rate and crystal growth of the precipitating compounds. Many modern drugs are hydrophobic and have poor solubility in water. Industrially anti-solvent crystallization using water has been extensively used to precipitate such drugs. Water has many advantages as an anti-solvent but
∗ Corresponding author. Tel.: +91 22 3361 2024; fax: +91 22 3361 1020. E-mail addresses: [email protected], [email protected] (P.R. Gogate). 0255-2701/$ – see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.cep.2012.04.005
employing water results in delayed mixing rate between the solution and anti-solvent because of the low miscibility of water in organic solutions. The low rate of mixing may limit the fast local supersaturation and hence can decrease the rate of nucleation and subsequent particle formation, which can lead to the formation of large crystals with a broad crystal size distribution [1,2]. In addition, the conditions involved in crystallization experiments strongly affect the particle formation mechanism and govern the resulting particle size and its distributions. Hence controlling crystal size and distribution has been the most important concern related to antisolvent crystallization processes involving water. Use of ultrasound offers an effective variable to control anti-solvent crystallization and overcome problems related to crystal size distribution. Ultrasound assisted crystallization has been generally described as sonocrystallization. In the past few decades researchers have found that, ultrasound can be effectively used in beneficial ways to control the different stages of crystallization operation including the nucleation and growth of crystals [3–8]. Ultrasound as an energy source has been shown to be capable of inducing nucleation at lower supersaturation than conventional agitation. Use of ultrasound can also reduce the metastable zone width and induction time required for onset of crystallization [6]. Ultrasound results in rapid and uniform mixing, improves crystal form and crystal size distribution and reduces the agglomeration. By adjusting ultrasound related variables such as the power density and ultrasonic
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duration accompanied with proper crystallization conditions, the mean size and size distribution of precipitated crystals can be effectively controlled. The products formed by sonocrystallization are superior to those obtained by conventional crystallization since the crystal size distribution obtained using ultrasound is narrow and agglomeration in most of the cases is found to be reduced without altering the crystallinity of crystals, which is desired particularly in pharmaceutical industry. Ultrasound has been used to change the crystal size distribution of the anti-solvent crystallization process [7,8]. Size reduction of the high energy materials during anti-solvent crystallization by conventional methods (mechanical means) is not safe as they are very sensitive to friction and impact and in such cases sonocrystallization can be effectively used [5]. Ultrasound increased the crystal growth rate of potash alum and it was also observed that the crystals grown under ultrasound were smaller than those produced in a non-insonated, stirred crystallizer [9]. The objective of this study was to investigate the effect of various process parameters on anti-solvent crystallization under silent condition and subsequently under the influence of ultrasound to understand the effect on the crystal size distribution. In this work anti-solvent crystallization of salicylic acid has been carried out using water as anti-solvent under silent condition (without ultrasound) and under the influence of ultrasound. The studies related to salicylic acid crystallization are quite important considering the dependency of the applications on the particle size distribution and some of the early studies on spherical crystallization of salicylic acid were by the group of Kawashima [10–12]. It has been established that initial temperature of the salicylic acid plays an important role in deciding the crystal size and it was reported that with an increase in the temperature, larger agglomerates with less spherical forms composed of larger crystals were obtained. Blandin et al. [13] have also investigated the mechanistic details of precipitation of salicylic acid and reported that at low supersaturation conditions in the stirred vessel, the primary nucleation is of heterogeneous type and the secondary nucleation is dominant, whereas homogeneous primary nucleation dominates in the T-mixer at high supersaturations. Nordström and Rasmuson [14] have also investigated the polymorphism in the crystallization of salicylic acid. A careful analysis of the earlier works related to salicylic acid crystallization indicates that none of the studies were based on the use of ultrasound to alter the particle size distribution and hence the novelty of the current work is clearly established. During anti-solvent crystallization under silent conditions, parameters like solution concentration, standing time, solvent–anti-solvent ratio, temperature, stirring speed and solution injection rate were optimized with an objective of obtaining the salicylic acid crystals with narrow crystal size distribution. The optimized set of conditions were then used under the influence of ultrasound to investigate the effect of ultrasound and ultrasound related variables on the crystal size distribution using ultrasonic bath. During sonocrystallization, ultrasound related variables (time of sonication, moment of application of ultrasound, power of ultrasound, and frequency of ultrasound) were optimized. The effect of mode of irradiation (exposing the solution to ultrasonic waves) was also investigated by using an ultrasonic horn (direct irradiation by virtue of horn being dipped in the solution) to compare with the results obtained by indirect irradiation using an ultrasonic bath. The intensification aspect in the current work deals with the use of alternate source of energy in the form of ultrasound for obtaining the desired particle size distribution. In the case of pharmaceutical industry, obtaining the desired narrow particle size distribution is very important and any batches not meeting the specifications would mean additional processing. Use of ultrasound can effectively eliminate the additional processing
17
as well as improve on the time of crystallization which can be considered as the intensification of the crystallization operation. 2. Experimental methods 2.1. Materials Salicylic acid (C7 H6 O3 ) was purchased from SD fine chemicals Ltd., India. Solvent used was ethanol (99.9%), due to its high miscibility with water and was, also purchased from SD fine chemicals Ltd., India. Distilled water was used as anti-solvent, which has been prepared in laboratory by all glass distilled water unit procured from Borosil Glass Ltd., India. 2.2. Apparatus and experimental procedure Fig. 1 shows the schematic of experimental apparatus used for anti-solvent crystallization of salicylic acid under silent conditions (without ultrasound). The main purpose of using agitation was to rapidly mix the solution of salicylic acid in ethanol with anti-solvent water. The apparatus consists of a two neck flat bottom cylindrical glass reactor with a capacity of 0.15 L. The reactor was a cylindrical vessel with a diameter of 0.05 m and maximum height of 0.10 m but the maximum liquid height was always restricted to 0.075 m for operational ease. A burette was placed just above the small neck of reactor supported by the metal stand, to add the solution of salicylic acid in ethanol into the reactor. A pitched-blade metal disk turbine (diameter of 0.03 m) rotated by an electric motor was inserted through the bigger neck as shown in the schematic, to agitate the solution in the reactor. The clearance of the agitator from the bottom of the reactor was 0.005 m. A constant temperature bath was assembled with the apparatus to maintain the temperature. In case of experiments involving ultrasonic bath (procured from Dakshin, Mumbai with a power range of 100–200 W and frequency of 40 kHz and 25 kHz), the two neck flat bottom cylindrical reactor was placed in ultrasonic bath which produces the ultrasonic waves irradiating the solution in reactor indirectly. The power of ultrasound is adjustable and can be varied from 100 to 200 W. The available
Fig. 1. Experimental apparatus used for silent condition: (A) two neck flat bottom cylindrical glass reactor, (B) pitched-blade disk turbine, (C) burette, (D) metal stand, and (E) constant temperature bath.
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generator is a dual frequency generator which can generate waves of 25 kHz and 40 kHz frequencies. In case of sonocrystallization using ultrasonic horn, the only change in apparatus as compared to apparatus used for conventional crystallization was that the stirrer was replaced by ultrasonic horn also procured from Dakshin, Mumbai. The generator can generate the ultrasonic waves of 40 kHz frequency and the power of horn was fixed at 138 W. The sonocrystallization using horn is different than using ultrasonic bath assembly, as in former case the irradiation are directly passed into the solution in reactor by directly immersing the tip of the horn in the solution, whereas in the case of ultrasonic bath, the transducers attached at the bottom of bath are not in contact with the solution. Indirect irradiation is preferred in case where metal contamination is strictly avoided especially in the case of pharmaceutical drugs. For the anti-solvent crystallization of salicylic acid under silent condition experiments were carried to study the effect of solution concentration at 0.1, 0.15 and 0.2 kg/L of salicylic acid in ethanol. First, the distilled water (quantity depends on solvent–anti-solvent ratio) was taken in reactor and bath temperature was maintained as desired. The water was agitated using the pitched-blade disk turbine for a while in order to ensure that the water should attain the bath temperature. Exactly 0.02 L solution (salicylic acid dissolved in ethanol) was then taken in burette and was added to anti-solvent drop wise until it was finished completely. The exact position of the injection was inside the liquid midpoint between the agitator position at the center (ultrasonic horn in the case of experiments with ultrasonic horn) and the wall of the reactor. As soon as the solution was added to water the solute experienced the supersaturation. The mixing with anti-solvent decreased the solubility of salicylic acid in ethanol and ultimately resulted in prompt precipitation. The solution was then allowed to stand for different time span ranged between 1 and 12 h to complete crystal growth. To study the effect of temperature on crystallization the bath temperature was varied from 25 to 35 ◦ C (total of 3 different operating temperatures). Experiments were also carried out in order to study the effect of solvent–anti-solvent ratio (1:2 and 1:3). The operating stirring speed was varied between 320 and 600 rpm in order to investigate the effect of degree of mixing. Apart from drop wise addition (0.2 mL/s); the solution was released into the anti-solvent at three different injection rates of 2, 4 and 6 mL/s, to study the effect of solution injection rate. A peristaltic pump (procured from Enertech, India) was used to vary the solution injection rate. These experiments were repeated under silent condition and under the influence of ultrasonic wave. The ultrasound was applied to the system during the solution injection and crystal growth stages. The crystallizing chamber was sonicated using an ultrasonic bath and an immersed probe described earlier. In the case of sonocrystallization, ultrasonic power output, irradiation time, and the moment of application of ultrasound were varied. Apart from these three variables, effect of frequency of ultrasound was also studied using ultrasonic bath at two different frequencies of 25 kHz and 40 kHz respectively. The obtained crystals from the conventional and ultrasound assisted crystallization processes were filtered using vacuum and dried in oven. At the scales of operation used in the present work, not much problems were encountered for the separation of crystals using filtration. The dried crystals were photographed using 10× optical zoom microscope for crystal shape and size analysis. The dimensions of the photographs and the resolutions were adjusted in such a way that sufficient clarity was obtained for exact analysis of the size of the crystals. Also number of photographs have been considered to check the reproducibility of the obtained data for the crystal size. The exact size as described in the work refers to the maximum dimension of the needle shaped crystals of salicylic acid. For obtaining the crystal size distribution, known amount of
dried crystals were photographed and analyzed using ImageJ software for size distribution. Again repetitive analysis has been done to get reproducible results for the size distribution and the mean size reported in the work. 3. Results and discussion 3.1. Effect of various parameters under silent conditions Experiments were carried out under silent conditions to study the effect of various parameters including solution concentration, standing time, solvent–anti-solvent ratio, temperature, stirring speed and solution injection rate. The aim of these experiments was to obtain a set of operating conditions which will produce crystals with improved form and lower average particle size with relatively narrow crystal size distribution. 3.1.1. Effect of standing time Experiments were carried out to study the effect of standing time described as the time for which the solution was kept agitated after the complete addition of solution from burette in the reactor. Effect of standing time was investigated by allowing the solution to stand for different time intervals such as 1, 2, 4, 8 and 12 h respectively. The solution concentration, solvent–anti-solvent ratio, temperature, stirring speed, solution injection rate were fixed at 0.1 kg/L, 1:2, 30 ◦ C, 320 rpm and 0.2 mL/s respectively. It was observed that the average particle size of salicylic acid crystals obtained was almost constant at around 320 m for different standing times. It indicates that the particle size was unaffected even if solution was allowed to stand for very long duration. Examination under microscope also revealed that the crystal form remains same during all experiments. Thus from these results; effective time of standing can be finalized as 1 h for further optimization experiments, concluding that it is sufficient for complete crystal growth. 3.1.2. Effect of solution concentration The effect of concentration of solution was investigated using three different concentrations. Solutions with 0.1, 0.15 and 0.2 kg/L concentrations were injected into the anti-solvent through burette at 0.2 mL/s. The stirring speed was kept fixed at 320 rpm. However temperature and solvent–anti-solvent ratio were also varied in order to study the effect of solution concentration at different temperature and solvent–anti-solvent ratio. The temperatures were 25 and 30 ◦ C while the different solvent–anti-solvent ratios used were 1:2 and 1:3 respectively. The solution was allowed to stand for 1 h for crystal growth. Fig. 2 shows the effect of solution concentration at two different temperatures. According to the figure, the average particle size of salicylic acid decreases with an increase in the solution concentration. However the effect is more at higher temperature. It can be seen that the reduction in average particle size is more at 30 ◦ C as compared to 25 ◦ C. These results can be justified by the dependency of nucleation process on solution concentration and temperature. Higher concentrations of solution should produce a higher degree of supersaturation upon the mixing with the antisolvent, and as a result, rate of nucleation increases. The high rate of nucleation represents the formation of a large number of nuclei per unit time and leads to an increase in the number of crystals. This could make the size of each crystal smaller resulting in a decrease in the average particle size [15]. Also, the nucleation rate increases with increase in temperature [16]. Hence at higher temperature the nucleation rates are higher which results in a decrease in particle size as explained earlier. Thus the combination of high concentration with high temperature results in more reduction in particle size than with relatively low temperature. As shown in Fig. 3, it was
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Table 1 Effect of solution injection rate on average particle size of salicylic acid crystals experiments were conducted at 30 ◦ C, with solution concentration of 0.1 g/mL, stirring speed of 320 rpm and solvent–anti-solvent ratio of 1:2. Solution injection rate (mL/s)
Average particle size (m)
0.2 2 4 6
320 390 392 394
process would indeed be dependent on the degree of temperature adjustments required in the process.
Fig. 2. Average particle size of salicylic acid crystals as a function of solution concentrations at different temperatures and 1:2 solvent–anti-solvent ratio, experiments were conducted at 320 rpm and solution injection rate of 0.2 mL/s. 25 ◦ C, 30 ◦ C.
found that the solution concentration has no effect on crystal form till the concentration of solution was 0.15 kg/L. It was observed that at 0.2 kg/L the obtained crystals were found with somewhat reduced width as compared to crystals obtained at 0.1 kg/L. 3.1.3. Effect of temperature The effect of temperature on crystal form and average particle size was investigated in the range of 25–35 ◦ C; at solution concentration of 0.1 kg/L, stirring speed of 320 rpm and solution injection rate of 0.2 mL/s respectively. The standing time allowed for crystal growth was 1 h and solvent–anti-solvent ratio used was 1:2. It was found that the temperature had no effect on crystal form and average particle size. The average particle size was 320 m at 25 ◦ C, 318 m at 30 ◦ C, and 316 m at 35 ◦ C respectively. However according to the theory of nucleation the nucleation rate is directly proportional to temperature. Effect of temperature on nucleation kinetics of ␣ l-glutamic acid was investigated in the range of 25–45 ◦ C and according to the results obtained, the nucleation rate was found to be increased with temperature [3]. Thus at higher temperature the average particle size of obtained salicylic acid crystals should reduce, but it was not the case in the present work as the average particle size is almost unaffected by increase in temperature. The reason for this is relatively small increment in operating temperature which was unable to alter the supersaturation significantly. As the effect of temperature on the particle size was not so significant, the further experiments have been performed at 30 ◦ C operating temperature as it was found to be matching with the ambient conditions and hence incorporated minimal load on the cooling or heating characteristics. The overall economics of the
3.1.4. Effect of solvent/anti-solvent ratio Solvent/anti-solvent ratio governs the supersaturation and hence the effect of solvent–anti-solvent ratio on crystal form and average particle size was investigated using two different solvent/anti-solvent ratios; 1:2 and 1:3 respectively. Other parameters like solution concentration, temperature, stirring speed, solution injection rate were fixed at 0.15 kg/L, 30 ◦ C, 320 rpm and 0.2 mL/s respectively. The standing time allowed for crystal growth was fixed at 1 h. It was observed that the crystal form remains unchanged even if the ratio was varied but the average particle size was significantly affected. The average particle size of salicylic acid crystals at 1:2 solvent–anti-solvent ratio was 260 m while the crystals obtained at 1:3 solvent–anti-solvent ratio had average particle size of 224 m. It indicates that the average particle was reduced as the solvent–anti-solvent ratio was increased. The reason for the reduction is increase in nucleation rate. Supersaturation is increased as a result of increment in ratio, since anti-solvent volume added goes up which leads to higher nucleation rate resulting in decrease in average particle size. 3.1.5. Effect of solution injection rate The effect of solution injection rate was investigated in the operating range of 0.2–6 mL/s. Other parameters like solution concentration, temperature, stirring speed, solvent–anti-solvent ratio were fixed at 0.1 kg/L, 30 ◦ C, 320 rpm and 1:2 respectively. The standing time allowed for crystal growth was 1 h. Interestingly it was found that the solution injection rate not only affects the average particle size but also the crystal form was altered. Table 1 represents the obtained average particle size for various solution injection rates. It can be observed from table that the increase in solution injection rate has increased the average particle size of salicylic acid crystals. However the increase in solution injection rate beyond 2 mL/s had no effect on average particle size of crystals. Fig. 4 shows the crystal form at different solution injection rate. The agglomeration was found to be significantly reduced at higher
Fig. 3. Effect of solution concentration on crystal form of salicylic acid; experiments were conducted at 30 ◦ C and, solvent–anti-solvent ratio of 1:2, stirring speed of 320 rpm and solution injection rate of 0.2 mL/s (a) at 0.1 g/mL, (b) at 0.15 g/mL, and (c) at 0.2 g/mL.
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Fig. 4. Effect of solution injection rate on crystal form of salicylic acid crystals, operating temperature of 30 ◦ C with solution concentration of 0.1 g/mL, stirring speed of 320 rpm and solvent–anti-solvent ratio of 1:2 (a) at 0.2 mL/s, (b) at 2 mL/s, (c) at 4 mL/s, and (d) at 6 mL/s.
injection rate and the rod shape habit of crystals was modified to needle shape habit. Study of transformation of thiazole derivative polymorphs revealed that, the addition rate of water added as antisolvent; to precipitate the thiazole derivative from methanol has found to be significantly affecting transformation at higher drug solution concentration [8]. In contrast to results obtained in this case, the increase in injection rate of drug solution has resulted in the reduction of particle size of roxithromycin crystals, when precipitated from solution in acetone using water as anti-solvent [7]. 3.1.6. Effect of stirring speed Effect of stirring speed on crystal form and average particle size was investigated in the range of 320–600 rpm; at solution concentration, temperature, solution injection rate of 0.1 kg/L, 30 ◦ C and 0.2 mL/s respectively. The standing time allowed for crystal growth was 1 h and solvent–anti-solvent ratio used was 1:2. The average particle size of salicylic acid crystals significantly decreased with an increase in stirring speed while the crystal form remained unaffected. The abrasion caused by the blades of pitched blade stirrer used for agitation increased as the rotation speed goes up resulting in decrease in average particle size. Enhanced agitation also ensured better mixing of solvent and anti-solvent. The average particle size of salicylic acid crystals obtained at 320 rpm was
320 m, at 500 rpm was 265 m and at 600 rpm the obtained size was 228 m. Increasing the speed of rotation beyond 600 rpm was not feasible in the present setup as it leads to splashing of the liquid onto the reactor walls giving problems in the overall crystallization operation and possibly errors in the measurements. Also, due to uneven distribution of the energy dissipations in the case of stirred reactor, it is expected that the quantum of fine particles generated will be higher leading to enhanced problems in filtration. Thus, in general, it might not be advisable to use very high speeds for crystallization operations. A brief analysis also indicated that when experiments were carried out with 0.1 kg/L solution concentration, 30 ◦ C operating temperature, 1:2 solvent anti-solvent ratio, 320 rpm as the speed of rotation and the solution injection rate of 2 mL/s, larger and uniform crystals were obtained when the solution was allowed to stand for one hour after its addition to anti-solvent. However the average particle size obtained was too large (390 m). This might cause the problems in downstream processing and also in terms of the final product characteristics mainly due to their needle shape and large particle size. It has also been observed that the degree of mixing and turbulence also decides the final mean crystal size and distribution. With an objective of obtaining lower mean size of crystals, experiments have been carried out using ultrasonic irradiation.
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3.2. Effect of ultrasound Ultrasonic bath and horn were used to investigate the effect of ultrasound on anti-solvent crystallization of salicylic acid. Initially experiments were targeted at investigating whether ultrasound application results in variation in the induction time for crystallization. 3.2.1. Conductivity study and effect of ultrasound on onset of crystallization Conductivity was monitored using a conductivity probe with digital display, and was recorded with respect to time to investigate the effect of ultrasound on onset of crystallization. The experiments were carried out using ultrasonic bath with 0.1 kg/L solution concentration, 30 ◦ C operating temperature, solvent–anti-solvent ratio of 1:2, 320 as speed of rotation and the anti-solvent injection rate of 0.2 mL/s. The reactor was placed in bath and initially solution was added to the reactor instead of anti-solvent (as in previous experiments). The anti-solvent was taken in burette and added to solution drop wise. The solution was irradiated with ultrasonic waves of 40 kHz for about two minutes from the addition of first drop of anti-solvent in the reactor. The conductivity probe was inserted to record the conductivity with respect to time. The experiments were repeated in the same manner but under silent condition. Fig. 5 shows the conductivity as a function of time under silent condition and under the influence of ultrasound. In both conditions initially the conductivity increased from initial value of 1.17 mmho and reached to a particular maximum value beyond which the conductivity decreased indicating onset of crystallization. The time taken to reach the limiting value of 2 mmho was 100 s under the influence of ultrasound whereas under silent condition was 140 s to reach the maximum value of 1.95 mmho. The results obtained revealed that the ultrasound brought the onset of crystallization at lower supersaturation [17–19]. The attributed mechanism was the enhanced micromixing which plays a major role in deciding the crystal quality which is very important in the case of pharmaceutical products. Also ultrasound can induce primary nucleation in nominally particle-free solutions and, noteworthy, at much lower supersaturation levels as compared to the conventional mechanical agitation based crystallization operation. Hem [20] have discussed in detail the possible reasons behind the improvement in crystallization using ultrasound including various theoretical explanations involving the action of inertial cavitation bubbles, cooling effect, pressure effect, segregation effect, and
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evaporation effect. All these effects sound reasonable and may in fact act in a complementary fashion to enhance the levels of supersaturation. Wohlgemuth et al. [21] investigated the mechanism details by replacing cavitation bubbles by gas bubbles to check if the bubble surface itself acts as nucleation center and found that process was influenced not only due to gassing, but also ultrasound effects played a major role in deciding the crystallization efficiency. Other possible reasons are cooling and evaporation effect due to the cavitational bubble generation. During cavitation bubble formation latent heat for evaporation is taken from surrounding liquid resulting in localized cooling which increases the supersaturation level. Also some quantum of liquid solvent is vaporized during the bubble formation, so that the concentration of solvent decreases locally. One more hypothesis governing the effects of ultrasound is based on the observation that the growth rate of a crystal in an ultrasonic field increases with the intensity of the ultrasound. 3.2.2. Effect of irradiation time Experiments for variation in sonication time were conducted with 0.1 g/mL solution concentration, 30 ◦ C operating temperature, 1:2 solvent–anti-solvent ratio, 320 rpm as the speed of rotation and the solution injection rate of 2 mL/s. Ultrasonic bath was used to irradiate the solution in the reactor. Ultrasound was applied as soon as the addition of solution to anti-solvent was started. Ultrasonic power used was 200 W and the frequency of ultrasound was 40 kHz. The duration of application of ultrasound was varied in the range from 1 to 10 min. Fig. 6 shows the effect of ultrasound on the crystal form. It was found that as the duration of ultrasound application was increased the average particle size significantly decreased, as shown in Table 2. The effect of power ultrasound was intense when it was applied for 3 min. The average particle size was reduced to 82 m under the influence of ultrasound from 392 m, which was obtained under silent condition. Similar effects of decrease in the particle size with the application of ultrasound as reported by many researchers [4–6]. Abbas et al. [22] have reported that the application of ultrasound to a crystallization process significantly reduced size of NaCl crystals and narrowed the size distribution. By varying temperature and sonication power output, the desired particle size (5 m) could be achieved [22]. As ultrasound was effective in decreasing the particle size significantly, it is important to give some idea about the relative power consumption in the case of ultrasonic horn as well as the silent conditions (power dissipation would be in the form of stirring). The actual power dissipation (based on the calorimetric investigations) in the case of ultrasonic bath was about 135 W/L whereas in the case of mechanical stirring the power dissipation into the liquid was around 1 W/L. Thus it appears that the power consumption in the case of ultrasonic reactors is substantially higher but in the case of pharmaceutical products the desired size distribution is very important which prompts towards the effective use of ultrasonic reactors even at commercial scale. Another distinct advantage of using ultrasound would be in terms of the fact that ultrasound can induce primary nucleation in Table 2 Effect of time of sonication of average particle size of salicylic acid experiments were conducted with 0.1 g/mL solution concentration, 30 ◦ C operating temperature, 1:2 solvent–anti-solvent ratio, 320 rpm as the speed of rotation and the solution injection rate of 2 mL/s with ultrasound at 200 W and 40 kHz.
Fig. 5. Effect of ultrasound on onset of crystallization, experiments were conducted at 0.1 g/mL solution concentration, 30 ◦ C operating temperature, solvent–antisolvent ratio of 1:2, 320 as speed of rotation and the anti-solvent injection rate of 0.2 mL/s. without ultrasound, with ultrasound.
Sonication time (min)
Average particle size (m)
0 1 2 3 5 10
392 252 140 82 54 50
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Fig. 6. Effect of ultrasound on the crystal form of salicylic acid, experiments were conducted with 0.1 g/mL solution concentration, 30 ◦ C operating temperature, 1:2 solvent–anti-solvent ratio, 320 rpm as the speed of rotation and the solution injection rate of 2 mL/s. (a) Without ultrasound and (b) with ultrasound at 200 W and 40 kHz when applied for 3 min.
nominally particle-free solutions and, noteworthy, at much lower supersaturation levels as compared to the conventional mechanical agitation based crystallization operation. The scale up of the ultrasonic reactors would be based in terms of using flow reactors (power dissipation per unit volume is expected to be lower) with multiple transducers attached to the reactor wall through which the solution will be flowing [23]. The design of systems with large numbers of transducers can give an acoustic pattern that is uniform and noncoherent above the cavitational threshold throughout the reactor working volume. The use of low-output transducers gives the additional advantage of avoiding the phenomenon of cavitational blocking (acoustic decoupling), which arises where power densities close to the delivery point are very high. In addition, these multi-transducer units very effectively concentrate ultrasonic intensity towards the central axis of the cylinder and away from the vessel walls, thus reducing problems of wall erosion and particle shedding. The vessel can be operated in batch mode or, for larger-scale work, in continuous mode whereby units can be combined in a modular fashion for “scale-out” and increased residence time. In summary, a plurality of low electrical and acoustic power (1–3 W/cm2 ) transducers produces 25–150 W/L, but ideally 40–80 W/L [23].
3.2.3. Effect of time of application of ultrasound Effect of time of ultrasound application has been investigated by applying ultrasound at different time since the moment of addition of solution to previously agitated solution, which is recorded as zero time. It was applied after various times from reference point for exactly 3 min with 0.1 kg/L solution concentration, 30 ◦ C operating temperature, 1:2 solvent–anti-solvent ratio, 320 rpm as the speed of rotation and the solution injection rate of 2 mL/s. It was found that the agglomeration is reduced only if the ultrasound was applied within 2 min from the addition of solution. If the application of ultrasound was started after more than 2 min from the moment when the addition of solution was started, obtained crystals were agglomerated and large in size. Fig. 7 shows the effect of moment of application of ultrasound on crystal form of salicylic acid. Park and Yeo [7] have also reported that the ultrasonic waves induced the reduction of particle size of roxithromycin only when it was applied to the solution at the initial stage of anti-solvent crystallization. In the case of anti-solvent crystallization, the initial mixing and the levels of supersaturation is very important and hence ultrasound must be introduced right at the point of the addition of the antisolvent to the system.
3.2.4. Effect of power of ultrasound Ultrasonic bath at 40 kHz was used to study the effect of power of ultrasound in the operating range of 100–200 W. The ultrasound was applied for 2 min from the moment of addition of solution. Experiments were conducted with 0.1 kg/L solution concentration, 30 ◦ C operating temperature, 1:2 solvent–anti-solvent ratio, 320 rpm as the speed of rotation and the solution injection rate of 2 mL/s. Table 3 shows the effect of power of ultrasound on average particle size. Abrasive effect of ultrasound was found to be more intense at higher power and the average particle size of salicylic acid crystals decreased significantly with an increase in power of ultrasound. It was reported by several researchers that increase in power of ultrasound has resulted in decreasing the particle size owing to the large effect at high power [5–7]. An increase in the power of ultrasound means that more number of cavitational events occur in the system with an enhanced degree of acoustic streaming [24–26] leading to an increase in the physical effects which control the crystallization operation in terms of avoiding agglomeration and also particle breakage. 3.2.5. Effect of frequency of ultrasound Effect of frequency of ultrasound was investigated using two different frequencies, 25 kHz and 40 kHz respectively. Ultrasonic bath at 200 W was used for sonication and ultrasound was applied for 2 min. Experiments were conducted with 0.15 kg/L solution concentration, 30 ◦ C operating temperature, 1:2 solvent–anti-solvent ratio, 320 rpm as the speed of rotation and the solution injection rate of 2 mL/s. The average particle size obtained under above conditions at 40 kHz was 259 m while an average particle size of 257 m was obtained at 25 kHz. It was found that the crystal form and crystal size was not affected by change in frequency [4]. The obtained results can be attributed to the fact that at both 25 kHz and 40 kHz operating frequencies, it is expected that the physical effects of cavitation events such as acoustic streaming accompanied with Table 3 Effect of power of ultrasound on average particle size, Experiments were conducted at 40 kHz and 2 min of sonication time with 0.1 g/mL solution concentration, 30 ◦ C operating temperature, 1:2 solvent–anti-solvent ratio, 320 rpm as the speed of rotation and the solution injection rate of 2 mL/s. Power of ultrasound (W)
Average particle size (m)
0 120 154 200
390 260 205 140
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Fig. 7. Effect of moment of application of ultrasound, with 0.1 g/mL solution concentration, 30 ◦ C operating temperature, 1:2 solvent–anti-solvent ratio, 320 rpm as the speed of rotation and the solution injection rate of 2 mL/s. (a) Ultrasound was applied as soon as the solution addition started and (b) ultrasound was applied after 4 min from the moment when addition of solution was started.
turbulence is dominant whereas the chemical effects will be dominant at much higher frequencies of irradiation (above 200 kHz). 3.2.6. Effect of direct irradiation (sonocrystallization using horn) Experiments were conducted to compare the effects of direct and indirect ultrasonic irradiation. Direct irradiation experiments were conducted using 40 kHz ultrasonic horn at 138 W, the tip of horn is directly immersed in anti-solvent, with 0.1 kg/L solution concentration, 30 ◦ C operating temperature, 1:2 solvent–antisolvent ratio, 320 rpm as the speed of rotation and the solution injection rate of 2 mL/s. The ultrasound was applied for 2 min and after that the solution was kept agitated by magnetic stirrer at moderate speed. It was observed that the effect of ultrasound is more when horn was used for irradiation instead of bath. The average particle size of crystal obtained was 146 m at 138 W while average particle size of 205 m was obtained with bath when the power of ultrasound was 154 W. It appears that use of ultrasonic horn gives better results at equivalent levels of power dissipation but the possibility of contamination due to the erosion of the horn tip needs to be explored before selecting the final mode of operation. In the case of pharmaceutical applications, any type of contamination must be strictly avoided and hence designs for scale up will be based on the flow cell type of configuration with transducers attached to the wall of the reactor. 4. Conclusions The present work have shown that various parameters like solution concentration, standing time, solvent–anti-solvent ratio, temperature, stirring speed and solution injection rate significantly affects the anti-solvent crystallization of salicylic acid from ethanol using water. The average particle size was found to decrease with an increase in solution concentration, stirring speed and solvent–anti-solvent ratio. The effect of temperature at solution concentration of 0.1 kg/L on average particle size was negligible. Increase in solution injection rate resulted in reduction in agglomeration and rod shape crystals turned into needle like structures. Optimization of the different variables gave the best set of conditions as 0.1 kg/L solution concentration, 30 ◦ C operating temperature, 1:2 solvent–anti-solvent ratio, 320 rpm as the speed of rotation and the solution injection rate of 2 mL/s. When antisolvent crystallization of salicylic acid was carried out using these conditions and allowing a standing time of 1 h, the obtained crystals were more uniform and crystal size distribution was improved. It has been clearly established that ultrasound can be effectively used to control the anti-solvent crystallization process in terms of the mean size of obtained crystals and its distribution. During
sonocrystallization experiments, ultrasound related variables like irradiation time, power of ultrasound, moment of application of ultrasound have been found to affect the crystal size distribution whereas frequency did not have much effect over the range of frequencies investigated in the present work. It was found that irradiation time and power of ultrasound decreased the average particle size. The moment of application of ultrasound is critical and it should be applied at the initial stage of crystallization. Experiments at 200 W using ultrasonic bath, applying ultrasound as soon as the addition of solution started for 2 min with ultrasound frequency of 25 kHz or 40 kHz, resulted in small crystal size and agglomeration was significantly reduced. The effect of ultrasound is more if the horn is used instead of ultrasonic bath though the possibility of the contamination needs to be explored. The power consumption in the case of ultrasound reactors appeared to be higher as compared to the stirred reactor but the main advantage will be in terms of improvement in the crystallization process which can lead to higher rates of processing with minimal rejection of the batches. Also, better particle size distribution will mean that rapid filtration can be obtained as the crystals of a more uniform size and compact habit can be filtered much more rapidly.
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