Sonofragmentation: Effect of Ultrasound Frequency and Power on

Article pubs.acs.org/crystal

Sonofragmentation: Effect of Ultrasound Frequency and Power on Particle Breakage Jeroen Jordens,†,‡ Tessa Appermont,‡ Bjorn Gielen,†,‡ Tom Van Gerven,*,† and Leen Braeken‡ †

Department of Chemical Engineering, KU Leuven, Celestijnenlaan 200F, B-3001 Leuven, Belgium Research Group Lab4U, Faculty of Industrial Engineering, KU Leuven, Universitaire Campus Gebouw B bus 8, 3590 Diepenbeek, Belgium

‡

ABSTRACT: This paper investigates, for the first time, the breaking mechanism of particles exposed to implosions of stable and transient cavitation bubbles via Kapur function analysis. The effect of ultrasonic frequencies of 30−1140 kHz and powers of 4−200 W on particle breakage of paracetamol crystals was studied. The dominant cavitation bubble type was defined via sonoluminescence measurements. The breakage rate of seed crystals with a median size of 75 μm was found to be independent of the applied power when ultrasonically generated stable cavitation bubbles were generated. Furthermore, a particle size threshold of ca. 35 μm was observed. The particle size could not be reduced below this size regardless of the applied power or frequency. For transient bubbles, in contrast, higher powers lead to considerably smaller particles, with no threshold size within the investigated power range. The Kapur function analysis suggests that stable bubbles are more efficient than transient bubbles to break coarse particles with sizes above 40 μm. Finally, cumulative breakage functions were calculated, and it was observed that transient bubbles generate more abrasion than stable bubbles.

1. INTRODUCTION Particle engineering, i.e., designing the particle size distribution and morphology of solids, is of particular interest for the production of poorly water-soluble drugs.1−3 It can improve the solubility, dissolution rate, and permeability of these drugs and hence increase their efficacy. Particle size reduction is one of the most studied strategies to achieve these effects as it increases the surface area to volume ratio of particles and hence their solubility and dissolution rate.4 Application of ultrasound is a promising technique to achieve this particle size reduction.5−9 Particle size reductions and narrower size distributions upon sonication are reported during several crystallization and precipitation processes.5,10−12 The effects of ultrasound can be attributed to the implosions of cavitation bubbles. Ultrasound irradiation of a solution results in pressure waves in the liquid which cause compression and rarefaction of liquid molecules. Above a critical pressure of about 1010 Pa, voids, called cavitation bubbles, will be created.13,14 In practice, however, impurities or microbubbles of dissolved gases will be present in the liquid. These bubbles act as nuclei and lower the required pressure for the creation of cavitation bubbles.15 The cavitation bubbles can be classified in two main types: stable and transient bubbles.13,16 The former will oscillate around their equilibrium radii for many acoustic cycles (50−200) and are long-lived.17 As a result, gases will be able to migrate through the bubble−liquid interface and enter the cavitation bubble. These gas molecules will absorb energy upon collapse and cushion the implosion. Transient bubbles, in contrast, © XXXX American Chemical Society

expand very rapidly to at least double their initial size. These bubbles exist for only a short time, typically less than one acoustic cycle. Because of this short time frame, the dissolved gases have insufficient time to cross the bubble−liquid interface and accumulate inside the bubble.18 The resulting lack of gas cushioning causes transient bubbles to implode very violently. The implosions of both stable and transient bubbles create, among other effects, shockwaves, high pressures (order of 1000 bar), microjets, and enhanced mixing.5,13,19 These effects impact the size of already formed particles by creating particle breakage (i.e., sonofragmentation).5,8 Although the application of ultrasound during crystallization and precipitation processes is well studied, sonofragmentation remains relatively unexplored.5,7,8,19 Most research in this topic is performed on inorganic solids in water.5,8,19 Raman and Abbas, for example, studied particle breakage of aluminum oxide particles suspended in water under sonication with a 24 kHz horn.20 The effects of ultrasonic powers of 150−350 W on breakage characteristics were investigated. Sonication with 350 W resulted in a 17% reduction in particle size after 5 min, compared to only ca. 13% size reduction at 150 W in the same time span. This inverse relation between the particle size and the applied power is also observed by other authors in the literature.20−23 Bartos et al., for example, studied the Received: January 19, 2016 Revised: August 24, 2016

A

DOI: 10.1021/acs.cgd.6b00088 Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

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sonofragmentation of the organic drug Meloxicam in water.21 A 24 kHz horn operating at 200 W was used to test the effect of sonication time, amplitude, temperature, and concentration on particle breakage during a two-level factorial design plan. A high amplitude (70% instead of 30%), long sonication time (30 min instead of 10 min), high temperature (36 °C instead of 0 °C), and low concentration (2 mg/mL instead of 18 mg/mL) were found to be important for the reduction of the median particle size. The most common explanation for the power effect on sonofragmentation is related to the implosion of cavitation bubbles. High powers will create large cavitation bubbles which will implode violently and hence create strong shockwaves, microjets, and turbulences which will eventually create particle breakage.13 Some research went more in detail to investigate which of these effects contributed most to particle breakage. Different mechanisms for the interaction between cavitation bubbles and particles were found for organic and inorganic molecules. Interparticle collisions are believed to be the main attributor to particle breakage upon sonication with inorganic solids.8,24 The shockwaves created upon implosion will accelerate the solid particles and cause high velocity collisions which then induce crystal breakage.24 For organic molecules, however, Zeiger and Suslick demonstrated that the mechanism for sonofragmentation differs.19 The authors studied four possible mechanisms: interparticle collisions, particle−horn collisions, particle−wall collisions, and particle−shockwave interactions. Microjets from asymmetric bubble collapse were not expected as the size of the cavitation bubbles (ca. 150 μm at 20 kHz) was larger than the size of the particles (ca. 30 μm).5,24 Aspirin crystals were suspended in dodecane and irradiated with an ultrasonic horn at 20 kHz and 10 W. They found that particle−shock wave interactions are the primary cause of particle breakage. In contrast to the inorganic particles, interparticle collisions seem to have an insignificant effect because higher particle concentrations did not result in more or faster breakage. These differences between organic and inorganic compounds are thought to be caused by different properties like friability, density, and tensile strength. Metal particles, for example, are malleable and are therefore not damaged by shock waves directly. These particles can only be affected by the more intense but much rarer interparticle collisions.19 Organic molecules, in contrast, are more friable and will therefore break by the impact of the shock waves. Although the effect of power on sonication is well studied, reports on the impact of frequency on particle breakage over a wide frequency range are scarce. Yamaguchi et al. studied the size reduction of liposome at frequencies of 43, 133, and 480 kHz.23 After 3 h of sonication, the mean diameter diminished from 300 nm to about 50 nm at a frequency of 43 kHz, while it decreased to only 200 nm at 480 kHz. On the basis of these two experiments, the authors concluded that a faster reduction of the mean size of liposome was achieved at lower frequencies. The results were explained by stronger shockwaves and microjets at lower frequencies. The power density and vessel design were, as also pointed by the authors themselves, not kept constant during their experiments. Furthermore, erosion of the ultrasonic bath introduced contaminants in the solution. Therefore, these results do not allow to draw univocal conclusions about the effect of frequency on sonofragmentation. Moreover, properties such as friability, density, and tensile strength of liposome are considerably different than those of organic molecules. This can result in different fragmentation

behaviors as this has already been observed in the case with inorganic and organic molecules. Several particle breakage models are presented in the literature varying from semiempirical models to more complicated population balance equations (PBE).22,25−29 Despite these numerous publications, only a few models were used to investigate ultrasound-facilitated particle breakage. Mainly two approaches are used in these papers, namely, PBE and Kapur function analysis.26,27,29 The main difference lies in the way the breakage distribution is provided. In PBE, a continuous breakage distribution function is used compared to a cumulative distribution function in Kapur function analysis.29 The main advantage of the latter lies in the simplicity of application to experimental results.30 Breakage and selection functions are used in these Kapur functions to characterize breakage. The breakage function (Bij) [−] gives the distribution of fragments created upon breakage of size fraction xj [μm]. The selection function Si [1/s] is the rate constant for breakage of particles of size xi [μm]. The cumulative distribution function used during Kapur function analysis for batch grinding can be written as26 p

R(x , t ) = R(x , 0)e[∑k =1 K

k

(x) t ] k!

(k)

(1)

where R(x,t) is the cumulative oversize fraction [%] above size x at any instant of time t [s], R(x,0) is the corresponding cumulative oversize fraction at the start of breakage [%] and x is the particle size class [−]. The term between brackets is known as the Kapur function from which the approximate selection function and breakage distribution functions can be derived. Furthermore, also a qualitative analysis of the breakage mechanism of the particles can be derived from this breakage function.26 In general, the main mechanism for particle size reduction can be characterized as either fracture or abrasion.26,31 The first mechanism, fracture, is defined as splitting of the original particle into variable-sized smaller particles and results in a broad particle size distribution.26,31 Abrasion, in contrast, is defined as the mechanism of size reduction by which significantly smaller particles are chipped away from the edges and surfaces of the original particles. Kapur function analysis allows researchers to differentiate in a qualitative manner between these two extreme forms of particle breakage. It does, however, not allow quantification of the percentage of abrasion or fracturing in the breakage process. This paper presents one of the first investigations on the effect of cavitation bubble type on the breakage mechanism of particles. Paracetamol was used as a model component for organic drug molecules. A broad frequency range of 30−1140 kHz was, for the first time, tested at a constant power density and vessel design. This allows investigation of the frequency effect on particle breakage and drawing of univocal conclusions. Furthermore, the dominant type of cavitation bubbles was determined by sonoluminescence measurements, and the effect of power on particle breakage was investigated for stable and transient bubbles. Finally, Kapur function analysis was performed to generate more insight into the breakage mechanism of particles exposed to the implosions of stable and transient bubbles.

2. MATERIALS AND METHODS 2.1. Experimental Setup. Figure 1 shows the experimental setup which consists of a jacketed glass cylinder without a top or bottom plate and an ultrasound transducer. The vessel has an internal diameter B



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applied stirring speed, no significant crystal breakage occurs. The stirrer was placed in the center of the vessel at 1 cm above the bottom. One ultrasonic horn and three ultrasonic transducers were used to test a frequency range of 30−1135 kHz. Table 1 shows the specifications of these ultrasonic sources. The ultrasonic horn was introduced from the top of the vessel in the solution, while the transducers are placed at the bottom. The ultrasonic frequency and power of the transducers were controlled by a Picotest G5100A waveform generator which was connected to an E&I 1020L RF power amplifier. Calorimetric power calibrations were performed to ensure that the power inside the vessel was constant for all different ultrasonic sources. This technique assumes that all power entering the solution is dissipated as heat.32 It does not allow calibration of the number of cavitation events, but several papers in the literature state that it allows reliable control of the total amount of power entering the solution.32−35 Therefore, this technique was used to compensate for differences in efficiency of power transfer among the different ultrasound sources. Correlations between the input power (Pin) and the calorimetric power (Pcal) can be obtained. Pin was defined as the difference between the forward and reflected power which could be obtained from the amplifier. These correlations are provided in Table 1 and show, in all cases, a linear relationship between the power transferred to the transducer or horn and the calorimetric power, with a linear correlation coefficient (R2) of at least 0.97. In this paper, these linear correlations are used to calculate the required Pin for a certain Pcal by interpolations within the tested power range of 4−200 W. The importance of calorimetric measurements during sonochemical experiments is already emphasized in the literature.35,36 2.2. Procedure Particle Breakage Experiments. A saturated solution of 4-acetamidophenol (98%, Acros Organics) in ultrapure water (18.2 MΩ.cm) was made at 25 °C. This solution was filtered over a 0.45 μm filter to remove all impurities. Afterward, 150 mL of this solution was introduced in the vessel. Next, stirring and ultrasound were switched on resulting in a temporary rise in temperature up to 30 °C. After the temperature had stabilized again at 25 °C, the experiment was started by adding 13 g of the paracetamol crystals to the solution. Samples of 7 mL were taken directly at the start of the experiment and after 10, 30, 60, 110, and 180 min. These samples were filtered over a 0.45 μm filter and dried for 24 h. Finally, the samples were analyzed for crystal size and shape with respectively a Malvern 3000 Mastersizer laser diffractometer and a Philips XL 30 FEG scanning electron microscope. The particles were suspended in hexane with 1% lecithin for the particle size measurements. Lecithin was added to prevent adhesion of paracetamol particles to the Mastersizer cell window.37 Silent experiments, with stirring and without sonication, were applied as a reference. 2.3. Procedure Sonoluminescence Experiments. Sonoluminescence (SL) quenching measurements were performed to define the dominant cavitation bubble type. In reality both stable and transient bubbles will be present in a sonicated solution, but one of them will be more dominant than the other. This technique has already been reported in several papers in the literature to define the dominant cavitation bubble type.38−40 The degree of quenching of SL signals, by adding volatile components, depends on the bubble type. Propanol will quench SL signals of stable cavitation bubbles, but not of transient bubbles. Acetone, on the contrary, will quench SL signals of both stable and transient bubbles and is added to ensure that these SL signals originate from cavitation bubbles. Ultrapure water (18.2 MΩ·cm) was used as the bulk medium and propanol (≥99.5%, Sigma-Aldrich) and acetone (≥99.8%, SigmaAldrich) are added, in separate experiments. Both alcohols were added in increasing concentrations up to 300 mM in steps of 50 mM until constant SL signals were obtained. These final SL values were used to determine whether stable or transient bubbles are present. SL signals were recorded for 30 s with a gate time of 100 ms, using a photon counting head (Hamamatsu, H11890 series). These SL signals were corrected for dark counts so that only the increase in photon counts caused by the sonoluminescence was taken as the SL value. Results are shown in this paper on a relative basis compared to the SL signal of ultrapure water (SL0). The threshold between transient and stable

Figure 1. Experimental setup. of 53 mm, an outer diameter of 83 mm, and a height of 97 mm. This transducer is placed at the bottom of the vessel and clamped to the cylinder to allow proper sealing of the vessel. By clamping different transducers to the bottom, each operating at their own resonance frequency, it is possible to use the same vessel over a wide frequency range. The solution temperature was fixed at 25 °C ± 1 °C by a Lauda ECO RE 415 thermostatic bath and external Pt100 temperature probe placed in the solution. A Cole Parmer ultra compact mixer with axial blade impeller of 30 mm diameter was used to stir the solution at 400 rpm. Stirring was applied during all experiments to avoid sedimentation of the particles at the bottom of the reactor. This stirring speed of 400 rpm was selected based on sedimentation experiments and allows good mixing, while sedimentation and particle breakage are avoided. The particle size was monitored for 180 min during a silent experiment to check possible breakage by the stirrer. Figure 2 shows the median particle size over time for this experiment. No significantly decreasing trend is visible from this graph, indicating the absence of breakage. All data points of the silent experiment are within the error bars which represent the standard deviation among seven different measurements. Hence, it was concluded that, at the

Figure 2. Median particle size (D50) as a function of time for different ultrasonic frequencies at a constant calorimetric power of 20 W. The error bars are based on the standard deviation obtained from the measurements of seven samples at time zero. The solid lines aid to detect the trend and do not represent any measurements or model. C



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Table 1. Overview of the Different Ultrasound Sourcesa

a

ultrasound source

type

frequency, kHz

diameter, mm

Hielscher UP50H Ultrasonics World MPI-7850D-20_40_60H Ultrasonics World MPI-7850D-20_40_60H Ultrasonics World MPI-4538D-40_100H Meinhardt E/805/T/M Meinhardt E/805/T/M Meinhardt E/805/T/M

horn transducer transducer transducer transducer transducer transducer

30 41 97 166 577 850 1140

7 78 78 40 75 75 75

linear equation Pcal 0.554Pin 0.636Pin 0.356Pin 0.355Pin 0.518Pin 0.474Pin 0.562Pin

+ 3.466 − 1.253 + 0.526 + 2.144 + 6.217 + 6.437 + 3.976

R2-value 0.99 0.98 0.99 0.97 0.99 0.99 0.99

The linear equations were used to calculate the calorimetric powers for input powers between 4 and 200 W.

Figure 3. Volume density after 180 min sonication at a constant calorimetric power of 20 W.

Figure 4. Number density after 180 min sonication at a constant calorimetric power of 20 W. relative SL signal of propanol is less than 50%. Oppositely, when the final SL signal of propanol remains above 50%, mainly transient

bubbles, defined as the 50% cutoff value, was set at 50% of this relative SL signal.38,39,41 Stable cavitation bubbles are dominant when the final D



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bubbles are present. It is not possible to quantify the exact amount of cavitation bubbles with this method. However, these relative SL signals allow us to roughly estimate the relative amount of transient bubbles compared to stable bubbles. High SL signals indicate a relatively large amount of transient bubbles compared to stable bubbles. Oppositely, low SL signals show up when more stable cavitation bubbles than transient bubbles are present.

break the initial particles as their particle sizes are similar to the sizes under silent conditions. In between these two zones lies a transition zone where some fragments are created by sonofragmentation, while the initial seed crystals are only marginally affected. In this zone, the degree of breakage decreases with increasing frequencies. At 577 kHz, for example, some fragments are created, but these have sizes in between the sizes obtained at 166 kHz and 850 kHz. These observations for particle size reduction are comparable to the size reductions reported by Yamaguchi et al.23 In their experiments significant breakage was observed at 43 and 133 kHz, while this was significantly less at 480 kHz. Also other papers in the literature have similar observations. Most articles report a significant particle size reduction with ultrasonic frequencies around 20 kHz, while no or less size reduction is reported for significantly higher frequencies.7,10,23,43 These trends can be explained by the strength of the shockwaves created upon implosion of cavitation bubbles. Zeiger and Suslick already showed that particle−shockwave interactions are the main source of particle breakage for molecular crystals.5 Low ultrasonic frequencies will generate large cavitation bubbles which implode violently and hence generate strong shockwaves and therefore cause particle breakage.5,13,23 High ultrasonic frequencies in contrast generate small bubbles which collapse less violently and hence generate weak shockwaves. Consequently, the degree of sonofragmentation will be low as well. The SEM images of all different frequencies were compared, but no significant effect of the frequency on the particle shape could be observed. Smaller particles were observed for the “low” frequencies, which supports the conclusions from the laser diffractometer measurements. Finally, the dominant cavitation type was defined for all frequencies according to the procedure described in section 2.3. Figure 5 shows the relative SL signal of propanol for the

3. RESULTS AND DISCUSSION First, the effects of ultrasonic frequency, power, and cavitation bubble type on particle breakage were investigated. Finally, these results are used to calculate the specific breakage rate and gain more insight in the mechanism of particle breakage via Kapur function analysis. 3.1. Impact of Ultrasonic Frequency. One set of experiments tested the effect of ultrasonic frequencies ranging from 30 to 1140 kHz on particle breakage. The calorimetric power was kept constant at 20 W. Figure 2 shows the median particle size (D50) of these experiments over 180 min. Two main trends can be observed from this graph: “low” frequencies show a significant decrease in particle size, while “high” frequencies do not result in particle breakage. The darkcolored curves represent the “low” frequencies of 166 kHz or below and show significant reductions in particle size. The initial particle size fluctuates, for all frequencies, around 65 μm and reduces to ca. 35 μm for these “low” frequencies. Small variations among the different “low” frequencies can be observed, but all curves tend to evolve toward an asymptotic particle size of ca. 35 μm. The light-colored curves, in contrast, representing frequencies of 577 kHz or above, do not show any significant decrease in particle size. Although these curves show larger fluctuations than the dark curves, the trends clearly differ from the plots of the “low” frequencies. After 180 min of sonication, the “low” frequencies created particles which are considerably smaller than the initial particles, while the “high” frequencies did not alter the original particle size significantly. This conclusion is further supported by Figure 3 where the particle size distributions of the final crystals are represented by a volume distribution. The two separate groups, representing the “low” and “high” frequencies, are clearly visible and separated from each other. This supports the finding that the initial particles are only reduced in size by frequencies of 166 kHz or below. The particle size distribution was also expressed in a number based distribution in Figure 4 to gain more insight in the frequency at which the sonofragmentation starts. This distribution gives the same weight to all particles, independent of their size, and makes it therefore easier to detect small fragments created by breakage even if the size of the initial particle is insignificantly impacted.42 Therefore, Figure 3 provides information about the size of the initial seed crystals, while Figure 4 shows if any fragments are created upon sonication. The two main groups of “low” and “high” frequencies are again present in Figure 4, but the frequency of 577 kHz lies now between both groups. Therefore, one can distinguish three zones: a low frequency, high frequency, and transition zone. The first zone covers frequencies of 30−166 kHz where significant breakage of the original particles occurs and a considerable amount of fragments with sizes around 1 μm is generated. The final size of these fragments is independent of the applied frequency and lies between 0.4 and 2.5 μm. The second zone, the high frequency zone, is present at frequencies above 850 kHz. These frequencies do not create fragments nor

Figure 5. Relative sonoluminescence signal of propanol at different frequencies and different calorimetric powers.

different frequencies. The frequency of 30 kHz showed SL signals significantly above 50%, indicating that primarily transient cavitation bubbles are present. At 30 W, a relative SL signal above 100% was obtained. Similar observations were made before in the literature, and these were attributed to the decrease in bubble coalescence yielding more SL active bubbles.41 All other frequencies in contrast show SL signals E



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Second a test with particles of 38−63 μm was performed, and finally particles of 63−125 μm were tested. All experiments were performed with a frequency of 97 kHz and power of 20 W. Figure 7 shows the evolution of the median particle size of

well below 50%, suggesting that stable bubbles were the dominant type. This indicates that a similar degree of particle breakage can be obtained by both stable and transient bubbles since both the transient bubbles at 30 kHz and the stable bubbles of 41, 97, and 166 kHz cause particle size reductions to a similar final particle size in the same time frame. 3.2. Impact of Ultrasonic Power. The effect of calorimetric power levels of 10, 20, and 30 W on particle breakage was tested for all frequencies except 166 kHz. As an example, Figure 6 shows the median particle size over 180 min

Figure 7. Evolution of the median particle size over time during sonication with a constant ultrasonic frequency of 97 kHz and calorimetric power of 20 W, for different initial particle size classes. The error bars are based on the standard deviation obtained from the measurements of seven samples at time zero. The solid lines aid to detect the trend and do not represent any measurements or model. Figure 6. Median particle size as a function of time for transient bubbles generated by the horn with a frequency of 30 kHz and for stable bubbles created by the ultrasonic transducer with a frequency of 41 kHz. The error bars are based on the standard deviation obtained from the measurements of seven samples at time zero. The solid lines aid to detect the trend and do not represent any measurements or model.

all three experiments in time. The particles smaller than 38 μm did indeed not vary in size during the course of the experiment, while the larger particles reduced in size toward the final median particle size of ca. 35 μm. The final particle size distribution of all experiments after 180 min sonication is shown in Figure 8. The largest peak of all curves overlaps,

for the transient bubbles generated by the 30 kHz horn and the stable bubbles of the 41 kHz transducer. For transient bubbles, higher power levels result in a faster decrease of the median particle size and significantly smaller final particles. Therefore, it can be concluded that the size reduction occurs faster and smaller final particles will be obtained at higher power levels for these bubbles. This is straightforward as higher powers generate more cavitation bubbles which will grow larger and hence collapse more violently.13,44 Consequently, this will create stronger shockwaves which will, according to the hypothesis of particle−shockwave interactions, generate higher breakage rates.5 These observations are also in agreement with the literature as faster size reductions and smaller final particles at higher power levels are frequently reported.7,8,20,23,45 In contrast, no significant effect of the power on particle breakage was observed for stable bubbles generated at 41 kHz. All data points are within the standard deviation of the experiments. The trends at 10, 20, or 30 W are comparable and evolve toward the same final particle size. Similar observations were made for all other frequencies with stable bubbles. The initial particle size is reduced, regardless of the power, to a final median size of ca. 35 μm. This indicates that a certain threshold size exists beyond which the particles cannot be further reduced by sonofragmentation. Three additional experiments, with different initial particle sizes, were performed to test the existence of a particle size threshold for stable bubbles. The first experiment consists of particles smaller than 38 μm which should not reduce in size when the particle size threshold exists.

Figure 8. Final particle size after 180 min sonication at constant ultrasonic frequency of 97 kHz and calorimetric power of 20 W.

which indicates that similar final particle sizes were achieved regardless of the initial size. Similar observations are reported by Ratoarinoro et al., who tested the effect of sonication on KOH particles with different initial size classes.46 A cup horn transducer operating at 20 kHz and 52 W was used, and the initial particle classes varied from 0 to 100 μm to 315−500 μm. All particles broke, independently of the initial size, to a final size of 15−20 μm. This final size is smaller than the 35 μm F



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favorable to generate a large amount of stable cavitation bubbles which implode weakly. When smaller particles are desired, transient bubbles creating strong shockwaves are needed to create sufficient breakage. Finally, the SEM images of the different powers were compared for transient and stable bubbles. No significant effect of the power on the crystal size or shape could be observed for the stable bubbles. Smaller particles were, in contrast, observed for transient bubbles at higher power levels which support the particle size measurements. Figure 9 shows the SEM images of

observed in this paper. However, inorganic KOH particles were used instead of organic paracetamol crystals, and the vessel design and applied frequency and power were different. The decrease in size followed a similar trend as shown in Figure 6. No explanation of these observations was, however, given. The results presented here, together with the results of Ratoarinoro et al., support the hypothesis that a particle size threshold exists. According to the hypothesis of particle−shockwave interactions, particles break into smaller parts by the stresses induced on the crystal lattice by the shockwaves. It is already reported in the literature that larger particles are easier to break than smaller particles.26,47 Among the possible explanations are the lower amount of defects, called Griffith cracks, present in the crystal lattice of small crystals compared to large particles or the larger torques applied on large particles compared to small particles.15 Therefore, the results in Figure 6 indicate that the initial particles are sufficiently large to break due to the shockwaves generated by the stable bubbles. Once these particles are reduced to a median size of around 35 μm, the stresses created by the shockwaves are too small to create further breakage by stable bubbles. This threshold value of ca. 35 μm is already achieved at 10 W after 180 min of sonication. Increasing the power does not result in smaller particles or faster reductions in size. It is hypothesized that the increase in power, for stable bubbles, only causes a marginal increase in shockwave intensity because of the gas cushioning. Higher powers will create more and larger cavitation bubbles, but these will be filled with more gas molecules which will cushion the implosions. Therefore, an increase in power is hypothesized to result in an insignificant increase in shockwave intensity for stable bubbles. Transient bubbles, in contrast, have no cushioning effect as explained in the introduction. Therefore, higher powers will generate more and larger bubbles, which will collapse more violently and generate more severe shockwaves. These bubbles have, therefore, the potential to exceed this threshold size as can be seen in Figure 6 during the experiment at 30 W. Final particles below 20 μm were achieved during this experiment. One can, however, not state as a general rule that transient bubbles are more efficient for sonofragmentation than stable bubbles. At calorimetric power levels of 20 W, the stable bubbles generate particles of a similar final size as the particles obtained by transient bubbles and at 10 W stable bubbles are even more efficient in reducing the particle size. The reason for this observation is unknown, but it is hypothesized that the amount of cavitation bubbles is responsible for these differences. A horn with a diameter of only 7 mm was used for the frequency of 30 kHz, while all transducers had diameters of 40−78 mm. Therefore, sonication was applied locally and only a small part of the vessel contains cavitation bubbles which could create shockwaves. The stable bubbles, in contrast, were generated by transducers with considerably larger diameters of 75−78 mm. Therefore, the whole vessel volume was sonicated which was confirmed by visual observation of cavitation bubbles all over the vessel. In contrast, cavitation bubbles were only detected in the zone under the horn for transient bubbles. Further research is needed to check if indeed more cavitation bubbles are present with the transducers compared to the ultrasonic horn. These observations indicate that the type, size, and amount of cavitation bubbles impact the shockwave intensity and hence particle breakage. A trade-off between the amount and the strength of implosions should be made when considering sonofragmentation efficiencies. At low powers it seems

Figure 9. SEM images of the particles after 180 min of sonication at 30 kHz with different ultrasonic powers. A 1000 times magnification is also displayed for 30 W.

the experiments with transient bubbles. Additionally, a particle shape transition from elongated particles to more spherical particles is visible upon increasing powers. This smoothening of particles by ultrasound was already observed in the literature and can be attributed to erosion caused by interparticle collisions or shockwaves.5,48 The reported studies used, however, inorganic particles where different mechanisms can be playing as described in the Introduction. Further research is therefore needed to confirm that interparticle collisions cause this smoothening also for organic particles. 3.3. Kinetic Modeling of Sonofragmentation. Kinetic modeling via the Kapur function was conducted to gain more insight in the breaking mechanism of particles. This kinetic modeling was performed according to the procedure provided in the literature.26 First, 10 logarithmically spaced particle size classes were chosen between 25 and 100 μm as provided in Table 2. Numbering of these classes is done in reverse order, where 10 refers to the finest particle size of 25−29.2 μm and 1 to the coarsest size of >100 μm. Next, the cumulative oversize fractions R(x,t) were calculated for each particle class. Subsequently, the residual ratios f(x,t) [−] were obtained by the following equation: f (x , t ) =

R (x , t ) R(x , 0)

(2)

where R(x,t) is the cumulative oversize fraction [%] above size x at any instant of time t [s], and R(x,0) the corresponding cumulative oversize fraction at the start of breakage [%]. For short grinding times, this equation can be reduced to G



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Table 2. Definition of Particle Size Classes particle class i,j

particle size range, μm

1 2 3 4 5 6 7 8 9 10

>100.00 85.7−100.0 73.5−85.7 63.0−73.5 54.0−63.0 46.3−54.0 39.7−46.3 34.0−39.7 29.2−34.0 25.0−29.2

f (x , t ) = e(K

(1)

t)

(3)

Figure 10. Specific breakage rate in function of particle size for the ultrasonic horn and 41 kHz transducer. The error bars represent the standard deviation on the measurements with five repetitions.

with K the first Kapur function [1/s] and t the actual grinding time [s]. Short or long grinding times are, however, relative terms that depend on the grindability of the material and the efficiency of the grinding equipment.49 Therefore, Kapur proposed the dimensionless time T, calculated by eq 4, as a more appropriate measure to define whether eq 3 can be used or not.49 (1)

T = [1 − e(−K

(1)

t)

]100%

However, an input power of max 50 W was used in this research compared to input powers of 150−350 W in the paper of Raman et al.26 Furthermore, organic paracetamol crystals are used in Figure 10 compared to Al2O3 particles in the article of Raman et al. The lower breakage rate for particles of 25 μm compared to particles of 100 μm confirms the observation made in section 3.2 that particle breakage depends on the particle size. As explained before, the larger amount of defects present or higher torque applied on larger particles provide possible explanations. Furthermore, higher ultrasonic powers result in higher specific breakage rates for the ultrasonic horn. This is consistent with the observations in the literature and can, as explained before, be attributed to more and heavier implosions of the cavitation bubbles.20,22,26 However, a considerably different trend can be noticed for the 41 kHz transducer. The specific breakage rate seems to be independent of the calorimetric power and depends only on the particle size. Only the frequency of 41 kHz is shown in Figure 10, as an example, but similar observations were made for the transducers of 97 and 166 kHz. As explained before, this higher breakage of larger particles compared to smaller particles can be attributed to the larger torques applied on the particles or the higher amount of defects present in these large particles. As stated before, it was hypothesized that gas cushioning diminishes the effect of power on the shockwave−intensity of stable cavitation bubbles so that an increase in power does not result in higher breakage rates. These observations are, moreover, valid for all different size classes as can be seen in Figure 11. The plots of the breakage rate as a function of the calorimetric power are quasi-horizontal for the 41 kHz transducer for all size classes. Only classes 1, 5, and 10 are shown in Figure 11, as an example, but similar trends could be observed for all other classes. This indicates that the breakage rate is independent of the power for the ultrasonic transducers. The breakage rates for the ultrasound the horn, in contrast, show a strong dependency on the power. At 10 W breakage rates of 8.2 × 10−6 to 3.8 × 10−5 [1/s] were observed compared to 10-fold higher breakage rates of 1.4 × 10−4 to 4.3 × 10−4 [1/s] at 30 W. Moreover, at 10 and 20 W, there is a significant difference in breakage rate for size classes 1−7 (sizes >39.7 μm) between the 41 kHz transducer and the horn. More than 2-fold higher breakage rates are obtained with the transducer compared to the horn for these particle size classes. Size classes 10, 9, and 8 (sizes 25−39.7 μm), in

(4)

This dimensionless time T corresponds with the percentage of feed crystals that are broken toward particle sizes smaller than these of particle class 1. According to Kapur, very long times (T > 95%) are not recommended for estimating the distribution parameters.49 Therefore, grinding times of 90 min were selected so that the dimensionless time T was, in all cases, smaller than 80%. Next, ln( f(x,t)) was plotted versus time for 90 min. The first Kapur function was obtained from the slopes of the ln( f(x,t)) time plots. Correlation coefficients, R2, of at least 0.9 were obtained for frequencies of 166 kHz or below. Frequencies of 577 kHz or above show only limited size reductions in time and have therefore slopes close to zero which resulted in very small R2 values. These frequencies are therefore not considered for further analysis. Finally, the specific breakage rate (Si) [1/s] and cumulative breakage function (Bi,j) [−] are, respectively, calculated by eqs 5 and 6.

Si = −K i(1) Bi , j =

(5)

K i(1) K (1) j

(6)

Figure 10 shows the specific breakage rate of the 30 kHz horn and 41 kHz transducer as a function of the particle size for the different calorimetric powers. The particle size presented in this figure corresponds to the minimum particle size of each particle size class. The breakage rate increases with the particle size for all experiments and the largest specific breakage rates are obtained for particles of 100 μm or above. Particles of 100 μm, for example, are broken by a specific breakage rate of 4.3 × 10−4 [1/s], when sonicated with a 30 W horn. In contrast, 25 μm particles show a 3 times lower breakage rate of only 1.4 × 10−4 [1/s] under the same conditions. The breakage rate for 25 μm is in the same range as the breakage rates observed in the paper of Raman et al. The breakage rate of 4.3 × 10−4 [1/s] for the particles of 100 μm, in contrast, is smaller than the breakage rate of 1 × 10−3 to 2 × 10−3 [1/s] obtained in the same paper. H



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effective in breaking finer particles which cannot be broken by stable bubbles. Further research is, however, needed to clarify whether indeed the difference in cavitation bubble type or the amount of bubbles or other differences between the probe and transducers are the cause for these observations. Figure 12 shows the specific breakage rate in function of the applied frequency at a constant calorimetric power of 20 W. The specific breakage rate of 577 kHz was obtained despite a very low R2 of 0.33 but is nevertheless provided for demonstration purposes. As no significant reduction in particle size could be observed at this frequency, the breakage rate is, as expected, close to zero. At first glance, one could observe an optimal frequency around 41 kHz where the specific breakage rates are maximized for all particle size classes. The specific breakage rate of class 1, for example, increases from 1.1 × 10−4 [1/s] at 30 kHz to 3.4 × 10−4 [1/s] at 41 kHz. A further increase in frequency, from 41 to 577 kHz for example, results in a reduction of the breakage rate to 1.8 × 10−6 [1/s]. The trend of 41−577 kHz can be explained by the cavitation bubble size. As explained before, low ultrasonic frequencies will generate larger bubbles, which will implode more violently and hence generate stronger shockwaves, turbulences, microjets, and higher pressures.13 The specific breakage rates at 30 kHz, however, are significantly lower and clearly deviate from the trend of increasing specific breaking rates with decreasing frequencies. The reason for this observation is unknown, but several possible explanations can be considered. As explained before, a lower number of cavitation bubbles was visually observed in the vessel compared to the other tests with the transducers. Therefore, fewer implosions and hence less particle breakage and lower breaking rates can be expected. Furthermore, the ultrasound field at 30 kHz is generated by an ultrasonic horn compared to ultrasonic transducers for all other frequencies. Mostly transient bubbles are present when applying the ultrasonic horn compared to stable bubbles for all transducers, as can be seen in Figure 5. The possibility exists that these transient bubbles break particles in a different way than stable bubbles.

Figure 11. Specific breakage rate in function of the calorimetric power for the ultrasonic horn and 41 kHz transducer at a calorimetric power of 20 W. The error bars represent the standard deviations on the measurements with five repetitions. Some error bars are smaller than the symbol size and are therefore not visible.

contrast, do not show a significant difference. Hence, the transducer seems to be more efficient than the horn to break particles above ca. 40 μm at these power levels. At 30 W, however, this effect reverses, especially for the fine particles in size classes 3 until 10 (sizes 25−73.5 μm). Particle size classes 5 and 10, for example, show at least 2 times higher breakage rate for the horn than the transducer at 30 W. Particle classes 1 and 2, in contrast, show no significant difference. It is hypothesized that the differences between the 40 kHz transducer and the 30 kHz horn can be attributed to the differences in cavitation bubble type (stable compared to transient). The introduction of the horn alone should not result in different breaking rates since particle−horn collisions are not considered as the main source for particle breakage of organic particles.19 Therefore, it is assumed that stable bubbles generated by the transducer are more efficient than the transient bubbles generated by the horn in breaking coarse particles, while transient bubbles are more

Figure 12. Specific breakage rate in function of the applied frequency at a constant calorimetric power of 20 W. The legend provides the particle size classes and the error bars the standard deviations based on five replicates. Error bars are only provided for classes 1, 5, and 10 for simplicity. The lines aid to detect the trend and do not represent any measurements or model. I



Article

above where no breakage occurred. Third, a transition zone which lies in between the two previous zones where some fines were created by the implosions of cavitation bubbles without significantly affecting the large crystals. Furthermore, this paper shows that similar particle breakage rates can be achieved with both stable and transient bubbles. However, the breakage rate of stable bubbles seems to be independent of the power, within the tested conditions, and a particle size threshold exists. The size of the particles cannot be reduced any further by increasing the power. This particle size threshold was not observed for transient bubbles. Moreover, the breakage rates of these transient bubbles depend strongly on the ultrasonic power. These results indicate that different breakage behaviors exist for stable and transient bubbles under the tested conditions. Finally, cumulative breakage functions were used to perform a qualitative analysis of fracturing or abrasion for both bubble types. Both fracture and abrasion were present during all experiments. Relatively more abrasion was, however, detected for transient bubbles compared to stable bubbles. Increasing powers led to more abrasion for the transient bubbles, while no effect on the breakage mechanism was detected for stable bubbles.

To investigate the breakage mechanism more in depth, the cumulative breakage functions are calculated and plotted in Figure 13 together with the Bi1 curves for abrasion and

Figure 13. Cumulative breakage function for transient and stable cavitation bubbles. The Bi1 curves for abrasion and fracturing are obtained from the literature.26

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fracturing obtained from the literature.26,31 This figure can be used to distinguish between two breaking mechanisms: fracture and abrasion. Figure 13 only allows a qualitative analysis of the breakage mechanism because fracture mechanisms can be quantified only by a detailed mass-balance analysis unlike abrasion which is primarily a surface mechanism.26 As shown in Figure 13, all curves lie in between the two extreme curves of abrasion and fracture, indicating that both mechanisms are present. This is expected and corresponds with observations made before in the literature.26 There are, however, differences between the curves for stable and transient bubbles. All cumulative breakage functions of the stable bubbles overlap. These curves are independent of the applied power and are close to the extreme curve for fracture, hence indicating that fracture will be the dominant breaking mechanism. Figure 13 shows only the breakage functions of the 41 kHz horn at 10 and 30 W, but similar curves are obtained at 20 W and at frequencies of 97 or 166 kHz. The cumulative breakage functions of the transient bubbles, in contrast, are shifted more toward the abrasion curves. Increasing the power shifts the curve even more to the abrasion curve, indicating that more abrasion occurs. These observations suggest that different breakage mechanisms exist for stable and transient bubbles under the studied experimental conditions. Stable bubbles seem to break particles mainly by fracture, and the power has no impact on the breakage behavior. Transient bubbles, in contrast, generate relatively more abrasion, and this abrasion is influenced by the applied calorimetric power. The higher the applied power, the more abrasion occurs.

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The research leading to these results has received funding from the European Community’s Seventh Framework Program (FP7/2007-2013) under Grant Agreement No. NMP2-SL2012-309874 (ALTEREGO). J.J. acknowledges funding of a Ph.D. grant by the Agency for Innovation by Science and Technology (IWT).

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4. CONCLUSION The effect of sonication over a broad frequency range of 30− 1140 kHz on particle breakage was, for the first time, tested in this study. Three different frequency zones were observed. First, a low frequency zone, with frequencies of 166 kHz or below where significant breakage of particles was observed. Second, a high frequency zone with frequencies of 850 kHz or J



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Sonofragmentation: Effect of Ultrasound Frequency and Power on

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