crystals

Review The Effects of Ultrasound on Crystals: Sonocrystallization and Sonofragmentation

Hyo Na Kim and Kenneth S. Suslick * Department of Chemistry, University of Illinois at Urbana-Champaign, 600 S. Mathews Av., Urbana, IL 61801, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-217-333-2794



Received: 11 June 2018; Accepted: 2 July 2018; Published: 4 July 2018


Abstract: When ultrasound is applied to a solution for crystallization, it can affect the properties of the crystalline products significantly. Ultrasonic irradiation decreases the induction time and metastable zone and increases the nucleation rate. Due to these effects, it generally yields smaller crystals with a narrower size distribution when compared with conventional crystallizations. Also, ultrasonic irradiation can cause fragmentation of existing crystals which is caused by crystal collisions or sonofragmentation. The effect of various experimental parameters and empirical products of sonocrystallization have been reported, but the mechanisms of sonocrystallization and sonofragmentation have not been confirmed clearly. In this review, we build upon previous studies and highlight the effects of ultrasound on the crystallization of organic molecules. In addition, recent work on sonofragmentation of molecular and ionic crystals is discussed.

Keywords: ultrasound; sonocrystallization; sonofragmentation; sonochemistry; acoustic cavitation; crystal nucleation

1. Introduction Ultrasound is an oscillating sound pressure wave over a frequency range of 15 kHz to 10 MHz [1]. When ultrasonic waves pass through a liquid with sufficient amplitude, the negative pressure exceeds the local tensile strength of the liquid and bubbles are created [2–4]. Bubbles are typically generated near pre-existing impurities (e.g., gas-filled crevices in dust motes), which oscillate and grow during cycles of compression and expansion. When the growing bubbles reach a specific resonant size, they efficiently absorb energy from ultrasound waves during a single compression-expansion cycle [1,5,6]. The resonant size depends on the frequency of the irradiated ultrasound, and is approximately 170 µm for a 20 kHz ultrasound [1]. At the resonant size, bubbles grow rapidly during a single cycle of ultrasound waves due to efficient energy absorption. Since bubbles cannot be sustained without absorption of energy, they implosively collapse after reaching the resonant size. This process is referred to as acoustic cavitation. There are both chemical and physical effects of acoustic cavitation. Ultrasonic wavelengths in liquid vary from approximately 1 mm to 10 cm, which is much larger than the molecular size scale. Thus, the chemical and physical effects of ultrasound do not occur by direct interactions between ultrasound and chemical species, but by the process of acoustic cavitation [2,4,7]. The collapse of bubbles produces hot spots, which have intense local temperatures (~5000 K) and pressures (~1000 atm) and a rapid heating and cooling rate (>1010 K·s−1)[8–11], and shockwaves. Shockwaves have velocities as high as ~4000 m/s and high-pressure amplitudes of 106·kPa [12]. The physical effects of ultrasound are more diverse in heterogeneous systems (solid-liquid systems) than in homogeneous systems. When a bubble collapses near a significantly larger surface or particle, the bubble no longer collapses spherically and a high-speed liquid stream with a velocity

Crystals 2018, 8, 280; doi:10.3390/cryst8070280 www.mdpi.com/journal/crystals Crystals 2018, 8, 280 2 of 20

>100 m/s is generated (i.e., a microjet) [13,14]. The liquid moves toward the surface of the solid material,Crystals which 2018, 8, deforms x FOR PEER it REVIEW or changes its chemical composition [1,15]. Additionally, shockwaves2 of 20 generated from acoustic cavitation cause high-velocity collisions between micron-sized solid particles (i.e., interparticle>100 m/s is generated collisions) (i.e., [16 –a 18microjet)]. Shockwaves [13,14]. Th cane liquid also directlymoves toward interact the with surface particles of the and solid induce material, which deforms it or changes its chemical composition [1,15]. Additionally, shockwaves breakage (i.e., sonofragmentation) [19]. generated from acoustic cavitation cause high-velocity collisions between micron-sized solid Sonocrystallizationparticles (i.e., interparticle is crystallization collisions) [16–18]. induced Shockwaves by ultrasound, can also and directly was firstinteract reported with particles by Richards and Loomisand induce in 1927 breakage [20]. In(i.e., that sonofragmentation) report, the author [19]. investigated the ultrasonic effects of crystallization, among otherSonocrystallization diverse physical is andcrystallization chemical induced influences. by ultrasound, From the 1950sand was to first the 1970s,reported sonocrystallization by Richards was activelyand Loomis studied in 1927 in the [20]. former In that Soviet report, Union the [author21–24 ].investigated Since that the time, ultrasonic sonocrystallization effects of of variouscrystallization, materials and among the modification other diverse ofphysical diverse and experimental chemical influences. parameters From have the 1950s been to reported the 1970s, [25 –27]. The industrialsonocrystallization use of sonocrystallization was actively studied increased in the former during Soviet the 1980sUnion due [21–24]. to advances Since that in time, ultrasonic sonocrystallization of various materials and the modification of diverse experimental parameters equipment, and, currently, sonocrystallization is common for generating crystals in the pharmaceutical have been reported [25–27]. The industrial use of sonocrystallization increased during the 1980s due and fineto advances chemicals in sectorsultrasonic [28 equipment,–30]. Despite and, considerablecurrently, sonocrystallization research, a fundamental is common for understanding generating of sonocrystallization,crystals in the pharmaceutical especially the and mechanism fine chemical of action,s sectors remains [28–30]. incomplete. Despite considerable research, a fundamental understanding of sonocrystallization, especially the mechanism of action, remains 2. Effectincomplete. of Ultrasound on Crystallization

2.1. Induction2. Effect Timeof Ultrasound and Metastable on Crystallization Zone Width Induction time (t ) is the elapsed time between supersaturation and the appearance of crystals 2.1. Induction Timeind and Metastable Zone Width (Figure1)[ 31]. It is composed of three parts, including the relaxation time (tr), stable nucleus time Induction time (tind) is the elapsed time between supersaturation and the appearance of crystals (tn), and nucleus growing time (tg). The relaxation time is the time required for the crystallized (Figure 1) [31]. It is composed of three parts, including the relaxation time (tr), stable nucleus time solution to achieve a quasi-steady-state distribution of molecular clusters, while the stable nucleus (tn), and nucleus growing time (tg). The relaxation time is the time required for the crystallized time andsolution nucleus to achieve growing a quasi-steady time are-state the timesdistribution required of molecular for the clusters, formation while of the a stablestable nucleus and its growthtime and to anucleus detectable growing size, time respectively. are the times In required some systems,for the formation especially of a stable those nucleus with a and low its degree of supersaturation,growth to a detectable massive size, nucleation respectively. occurs In some following systems, a latentespecially period those (t withlp). Thea low concentration degree of of the crystallizedsupersaturation, solution massive remains nucleation relatively occurs constantfollowing duringa latent period the induction (tlp). The concentration time and latent of the period. Followingcrystallized the latent solution period, remains widespread relatively crystal constant growth during occurs the induction and the concentrationtime and latent of period. the solution changesFollowing rapidly the and latent significantly. period, widespread Induction crystal time grow isth measured occurs and by the visual concentration observation of the solution or analytical changes rapidly and significantly. Induction time is measured by visual observation or analytical techniques that utilize conduction measurements or laser light scattering. There are several factors that techniques that utilize conduction measurements or laser light scattering. There are several factors affect inductionthat affect induction time measurements time measurements greatly greatly such as such agitation, as agitation, impurities, impurities, solution solution viscosity, viscosity, level of supersaturation,level of supersaturation, etc. etc.

Figure 1. A desupersaturation curve. There is lag time between the points of supersaturation (A) and Figure 1. A desupersaturation curve. There is lag time between the points of supersaturation (A) nucleation (B’). Initial nuclei grow until they are a detectable size (B). The concentration of the and nucleationsolution remains (B’). Initial relatively nuclei constant grow for until some they time are (C) a and detectable then it changes size (B dramatically). The concentration (D) due to of the solutionrapid remains crystal relatively growth. Finally, constant it forreaches some the time equilibrium (C) and thenconcentration it changes (E). dramatically C* = equilibrium (D) due to

rapid crystalsaturation, growth. tn = nucleation Finally, time, it reaches tind = induction the equilibrium time, and concentration tlp = latent period (E). [31]. C* = equilibrium saturation, tn = nucleation time, tind = induction time, and tlp = latent period [31].

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UltrasonicCrystals 2018, 8 irradiation, x FOR PEER REVIEW reduces induction time due to the improved micro-scale mixing3 of 20 and turbulence caused by acoustic cavitation. When the induction time decreases, the rate of appearance CrystalsUltrasonic 2018, 8, x FOR irradiation PEER REVIEW reduces induction time due to the improved micro-scale mixing3 ofand 20 of crystalsturbulence accelerates. caused Thus,by acoustic thenumber cavitation. of When produced the induction crystals time increases, decreases, while the rate their of sizes appearance decrease. Theof crystals effectUltrasonic accelerates. of ultrasoundirradiation Thus, reduces the on number the induction induction of produc timeed timedue crystals to for the increases, crystallizationimproved while micro-scale their has sizes previouslymixing decrease. and been reportedturbulence[32The–34 effect ]caused. Z. of Guo ultrasound by acoustic et al. studied on cavitation. the induction the When effects time the of inductionfor ultrasound crystallization time decreases, on has induction previously the rate time ofbeen appearance using reported saturated roxithromycinof[32–34]. crystals Z. solutions accelerates. Guo et [33al. Thus,]. studied In the this number study,the effects of saturated produc of ultrasounded roxithromycin crystals increases,on induction solutions while timetheir were sizesusing mixed decrease. saturated with water (antisolvent)roxithromycinThe under effect ofsolutions ultrasonic ultrasound [33]. irradiation on In the this induction study, and thesa timeturated induction for crystallizationroxithromycin time was has solutions assessed previously were using been mixeda reported He–Ne with laser [32–34]. Z. Guo et al. studied the effects of ultrasound on induction time using saturated recorder.water Notably, (antisolvent) induction under timeultrasonic was irradiation reduced whenand the sonocrystallization induction time was assessed was performed using a He–Ne (Figure 2). roxithromycinlaser recorder. solutionsNotably, [33].induction In this time study, was sa reducedturated roxithromycinwhen sonocrystallization solutions were was mixed performed with Additionally, the difference in induction time between sonocrystallization and stirring crystallization water(Figure (antisolvent) 2). Additionally, under theultrasonic difference irradiation in induction and the time induction between time sonocrystallization was assessed using and a stirringHe–Ne increasedlasercrystallization as recorder. the supersaturated increased Notably, asinduction the ratio supersat of time theurated solutionwas ratioreduced decreased.of the when solution sonocrystallization decreased. was performed (Figure 2). Additionally, the difference in induction time between sonocrystallization and stirring crystallization increased as the supersaturated ratio of the solution decreased.

Figure 2. Influence of ultrasound on the induction time (tind) of roxithromycin solutions with Figure 2. Influence of ultrasound on the induction time (tind) of roxithromycin solutions with different different supersaturated ratios (S) in the presence (▲) and absence (■) of ultrasound [33]. Ultrasonic supersaturated ratios (S) in the presence ( ) and absence ( ) of ultrasound [33]. Ultrasonic frequency Figurefrequency 2. wasInfluence unspecified, of ultrasound but an ultrasonic on Nthe induction horn was used,time so(tind one) of must roxithromycin assume ~20 solutionskHz. with was unspecified,different supersaturated but an ultrasonic ratios (S) horn in the was presence used, so(▲ one) and must absence assume (■) of ~20ultrasound kHz. [33]. Ultrasonic frequencyThose authors was unspecified, also assessed but thean ultrasonic induction horn time was of used,BaSO so4 under one must ultrasonic assume ~20irradiation kHz. and found that the induction time of sonocrystallization was shorter than that for stirring crystallization [35]. Those authors also assessed the induction time of BaSO4 under ultrasonic irradiation and found Those authors also assessed the induction time of BaSO4 under ultrasonic irradiation and found that theFurthermore, induction it time was ofconfirmed sonocrystallization that sonication was with shorter high-amplitude than that ultrasound for stirring waves crystallization decreased [35]. thatinduction the induction time more time than of sonicationsonocrystallization with low-amplitude was shorter waves than that(Figure for 3).stirring crystallization [35]. Furthermore,Furthermore, it was it was confirmed confirmed that that sonication sonication withwith high-amplitude ultrasound ultrasound waves waves decreased decreased inductioninduction time time more more than than sonication sonication with with low-amplitude low-amplitude waves waves (Figure (Figure 3).3 ).

Figure 3. Influence of ultrasound on the induction time (tind) of BaSO4 solutions with different supersaturated ratios (S). The amplitude of an 750 W ultrasonic processor was modified to 0% (♦, no Figureultrasound), 3. Influence 21% (■ of), 31%ultrasound (▲), 41% on the(×), induction51% (*), andtime 61% (tind )( ●of) [35].BaSO Ultrasonic4 solutions frequencywith different was Figure 3. Influence of ultrasound on the induction time (tind) of BaSO4 solutions with different supersaturatedunspecified, but ratios an ultrasonic (S). The amplitudehorn was used, of an so750 one W mustultrasonic assume processor ~20 kHz. was modified to 0% (♦, no supersaturated ratios (S). The amplitude of an 750 W ultrasonic processor was modified to 0% ultrasound), 21% (■), 31% (▲), 41% (×), 51% (*), and 61% (●) [35]. Ultrasonic frequency was (, nounspecified, ultrasound), but 21%an ultrasonic (), 31% horn (N was), 41% used, ( ×so), one 51% must (*), assume and 61%~20 kHz. ( )[ 35]. Ultrasonic frequency was unspecified, but an ultrasonic horn was used, so one must assume ~20 kHz. Crystals 2018, 8, 280 4 of 20 Crystals 2018, 8, x FOR PEER REVIEW 4 of 20

The metastable metastable zone zone width width (MZW) (MZW) is the is area the areabetween between an equilibrium an equilibrium saturation saturation curve and curve the andexperimentally the experimentally observed observed supersaturation supersaturation point at which point nucleation at which nucleation occurs spontaneously occurs spontaneously (Figure 4) (Figure[31]. For4)[ the31 generation]. For the generation of crystals, of the crystals, status the of a status solution of a changes solution from changes stable from to stablemetastable to metastable to labile to(unstable). labile (unstable). There are Thereseveral are ways several to generate ways to crystals, generate including crystals, cooling including (ABCD cooling line), (ABCD evaporation line), evaporationor addition of or an addition antisolvent of an (AB’C’ antisolvent line), a (AB’C’ combination line),a of combination cooling and ofevap coolingoration, and or evaporation, cooling and orthe cooling addition and of thean antisolvent addition of (AB’’C’’ an antisolvent line). (AB”C” line).

Figure 4.4. Solubility–supersaturationSolubility–supersaturation diagram. diagram. Solid Solid line line is ais solubilitya solubility curve curve ofa of solution. a solution. Dashed Dashed line isline a supersaturationis a supersaturation curve which curve represents which represents temperatures temperatures and concentrations and concentrations at which uncontrolled at which spontaneousuncontrolled crystallizationspontaneous crystallization occurs [31]. occurs [31].

When aa solutionsolution isis ultrasonicallyultrasonically irradiated,irradiated, thethe MZWMZW decreases.decreases. During sonocrystallization,sonocrystallization, gas-filledgas-filled crevices surrounding surrounding dust dust motes motes behave behave as as new new nucleation nucleation sites sites causing causing an anincrease increase in the in therate rateof nucleation of nucleation [36,37]. [36,37 ].Additionally, Additionally, micros microscalecale mixing mixing and and turbulence turbulence improves improves from thethe collapse ofof bubblesbubbles duringduring sonocrystallizationsonocrystallization [[38–41].38–41]. They accelerate diffusion of solutes andand increaseincrease thethe nucleationnucleation rate. Due to such increased nucleation nucleation site sitess and and improved improved mixing mixing efficiency, efficiency, sonocrystallization reducesreduces the the MZW. MZW. Mixing Mixing efficiency efficiency can be can formulated be formulated in terms ofin theterms Richardson of the fluxRichardson constant flux [42], constant a dimensionless [42], a numberdimensionless defined number as the ratio defined of buoyancy as the ratio to shear of termsbuoyancy in turbulence to shear kineticterms energyin turbulence equations. kinetic Lewis energy Fry Richardson equations. is alsoLewis familiar Fry forRichardson his observation is also that familiar turbulence for canhis beobservation described that as turbulence can be described as • • BigBig whorlswhorls havehave littlelittle whorlswhorls • That feed on their velocity, • That feed on their velocity, • And little whorls have lesser whorls • And little whorls have lesser whorls • And so on to viscosity. [43] • And so on to viscosity [43]. The effects of ultrasound on the MZW were confirmed during the crystallization of p-aminobenzoicThe effects acid of ultrasound(PABA) [44]. on Cooling the MZW crystalli werezation confirmed of PABA during was performed the crystallization at a constant of pcooling-aminobenzoic rate of acid1 °C/min (PABA) during [44]. Cooling sonication crystallization or with ofstirring. PABA wasThe performed nucleation at atemperature constant cooling was ◦ ratedetermined of 1 C/min by detecting during sonication the appearance or with of stirring. the firstThe crystals nucleation becoming temperature visible to was the determinednaked eye. As by detectingshown in theFigure appearance 5, nucleation of the occurred first crystals at lower becoming levels visible of saturation to the naked during eye. sonication As shown compared in Figure 5to, nucleationstirring. occurred at lower levels of saturation during sonication compared to stirring.

Crystals 2018, 8, 280 5 of 20 CrystalsCrystals 20182018,, 88,, xx FORFOR PEERPEER REVIEWREVIEW 55 ofof 2020

FigureFigure 5.5.5. EffectEffectEffect ofof ultrasoundultrasound onon the the metastable metastable zone zone width width (MZW)(MZW) ofof ppp-aminobenzoic-aminobenzoic-aminobenzoic acidacidacid 2 crystallization.crystallization. ForFor sonocrystallization, sonocrystallization, 20 20 kHz kHz andand 2.12.12.1 W/cmW/cmW/cm22 ofof ultrasoundultrasound waswas used.used.used. For For thethe unsonicatedunsonicated cases,cases, aa magneticmagnetic stirringstirring barbarbar waswaswas usedusedused to toto stir stirstir the thethe solution solutionsolution at atat 300 300300 rpm rpmrpm [ [44].44[44].].

Another example of a reduction in MZW under sonication is the antisolvent crystallization of AnotherAnother exampleexample ofof aa reductionreduction inin MZWMZW underunder sonicationsonication isis thethe antisolventantisolvent crystallizationcrystallization ofof benzoic acid [45]. A saturated benzoic acid solution was prepared using absolute ethanol, and mixed benzoicbenzoic acidacid [[45].45]. AA saturatedsaturated benzoicbenzoic acidacid solutionsolution waswas preparedprepared usingusing absoluteabsolute ethanol,ethanol, andand mixedmixed with water (antisolvent) by either conventional magnetic stirring or ultrasonic irradiation at room withwith waterwater (antisolvent)(antisolvent) byby eithereither conventionalconventional magneticmagnetic stirringstirring oror ultrasonicultrasonic irradiationirradiation atat roomroom temperature. As shown in Figure 6, the MZW decreases significantly on ultrasonic irradiation of the temperature.temperature. AsAs shownshown inin FigureFigure6 6,, the the MZW MZW decreases decreases significantly significantly on on ultrasonic ultrasonic irradiation irradiation of of the the benzoic acid solution. benzoicbenzoic acidacid solution.solution.

Figure 6. Simulated and experimental results of MZW change of benzoic acid with various addition FigureFigure 6.6. SimulatedSimulated andand experimentalexperimental resultsresults ofof MZWMZW changechange ofof benzoicbenzoic acidacid withwith variousvarious additionaddition ratesrates ofof antisolventantisolvent ((aa)) withwith stirringstirring (a(a magneticmagnetic bar,bar, 400400 rpm)rpm) andand ((bb)) underunder sonicationsonication (20(20 kHz,kHz, 88 rates of2 antisolvent (a) with stirring (a magnetic bar, 400 rpm) and (b) under sonication (20 kHz, W/cm 2). For each graph, the Eq conc line is the solubility curve of benzoic acid [45]. 8W/cm W/cm).2 For). For each each graph, graph, the the Eq Eq conc conc line line is isthe the solubility solubility curve curve of ofbenzoic benzoic acid acid [45]. [45 ]. 2.2. Nucleation Rate 2.2.2.2. NucleationNucleation RateRate Ultrasound may promote nucleation by reducing the critical excess free energy (ΔGcrit). When UltrasoundUltrasound may may promote promote nuclea nucleationtion by by reducing reducing the thecritical critical excess excess free energy free energy (ΔGcrit). (∆ WhenG ). ultrasound is irradiated to a solution, bubbles are generated [2–4]. At the bubble–solution interface,crit Whenultrasound ultrasound is irradiated is irradiated to a solution, to a solution, bubbles bubbles are gene arerated generated [2–4]. At [ 2the–4 ].bubble–solution At the bubble–solution interface, half a solute molecule is solvated by the solvent, while the other half is not due to contact with the interface,half a solute half molecule a solute moleculeis solvated is by solvated the solvent, by the while solvent, the while other thehalf other is not half due is to not contact due to with contact the bubble. Such contacts decrease the solvation rate. Re-dissolution of the solute molecule is then withbubble. the Such bubble. contacts Such contactsdecrease decrease the solvation the solvation rate. Re-dissolution rate. Re-dissolution of the ofsolute the solute molecule molecule is then is prevented, increasing the coagulation of molecules in the solution [46]. Thus, the critical excess free thenprevented, prevented, increasing increasing the coagulation the coagulation of molecules of molecules in the in solution the solution [46]. [ 46Thus,]. Thus, the critical the critical excess excess free energy (ΔGcrit) for nucleation is reduced, while the nucleation rate increases [31,37]. freeenergy energy (ΔG (crit∆)G for )nucleation for nucleation is reduced, is reduced, while while the nucleation the nucleation rate rateincreases increases [31,37]. [31, 37]. Also, ultrasoundcrit increases the rate of secondary nucleation by affecting the number of Also,Also, ultrasoundultrasound increases increases the the rate rate of secondary of secondary nucleation nucleation by affecting by affecting the number the of number secondary of secondary nucleation sites. Under ultrasonic irradiation, the crystals generated from primary nucleationsecondary sites.nucleation Under ultrasonicsites. Under irradiation, ultrasonic the irradiation, crystals generated the crystals from primarygenerated nucleation from primary collide nucleationnucleation collidecollide oror interactinteract withwith shockwavesshockwaves [47–49].[47–49]. DueDue toto thesethese ooccurrences,ccurrences, pre-existingpre-existing crystalscrystals areare fragmentedfragmented andand becomebecome sitessites ofof secondarysecondary nucleationnucleation [36,50].[36,50].

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orCrystals interact 2018, with8, x FOR shockwaves PEER REVIEW [47 –49]. Due to these occurrences, pre-existing crystals are fragmented6 of 20 and become sites of secondary nucleation [36,50]. ChowChow et al. investigated investigated sonocrystallization sonocrystallization of of ic icee crystals crystals in insucrose sucrose solution, solution, which which formed formed ice icedendrites dendrites (Figure (Figure 7)7 [51–53].)[ 51–53 ].Primary Primary nucleation nucleation produced produced the the ice ice dendrites, dendrites, which subsequentlysubsequently fragmentedfragmented duedue to to continuous continuous sonication. sonication. During During prolonged prolonged sonication, sonication, secondary secondary nucleation nucleation occurred aroundoccurred the around fragmented the fragmented crystals and crys cavitationtals and cavitation spots. From spots. corresponding From corresponding images ofimages these of events, these itevents, was confirmed it was confirmed that ultrasound that ultrasound affected affe primarycted primary and secondary and secondary nucleation nucleation events. events.

FigureFigure 7.7. OpticalOptical micrographs micrographs of of sonocrystallization sonocrystallization and and sonofragmentation sonofragmentation of ofice ice dendrites dendrites in ina 15 a 15wt wt % %sucrose sucrose solution solution using using 67 67 kHz kHz ultrasound ultrasound in in a acustom custom optical optical microscope microscope chamber. chamber. ( a) Primary nucleationnucleation and crystal growth (no(no ultrasound),ultrasound), (b)) flowflow patternspatterns andand breakagebreakage ofof iceice dendritesdendrites afterafter 1.361.36 ss ofof sonication,sonication, ((cc)) sonofragmentationsonofragmentation ofof iceice crystalscrystals afterafter 2.382.38 ss ofof sonication,sonication, andand ((dd)) secondarysecondary nucleationnucleation andand crystalcrystal growthgrowth afterafter 17.3817.38 ss ofof sonicationsonication [[51].51].

2.3.2.3. Polymorphism PolymorphismsPolymorphisms can bebe effectedeffected byby sonocrystallization.sonocrystallization. Polymorphism is the ability of a solidsolid materialmaterial toto existexist inin more thanthan oneone formform oror structurestructure [[54].54]. Polymorphs have different stabilitiesstabilities under certaincertain conditions,conditions, and the preferredpreferred formform dependsdepends onon thethe conditioncondition inin whichwhich thethe polymorphspolymorphs areare formedformed oror stored.stored. ItIt isis unknownunknown howhow ultrasoundultrasound controlscontrols thethe polymorphismpolymorphism ofof aa materialmaterial [[55–57].55–57]. SonocrystallizationSonocrystallization generally converts converts crystals crystals from from their their kinetically kinetically favored favored form form to to one one that that is isthermodynamically thermodynamically favored. favored. A typical A typical example example is th isat thatof calcium of calcium carbonate, carbonate, which which exists existsin three in threedifferent different forms forms including including calcite calcite (the (the most most stab stablele form form under under ambient ambient conditions), aragonitearagonite (metastable),(metastable), and vaterite vaterite (the (the least least stable stable form form)) [58]. [58]. Without Without sonication, sonication, vaterite, vaterite, which which is the is thekinetically kinetically favored favored form, form, was was generated. generated. Howeve However,r, the the percentage percentage of of calcite, calcite, which which is is thethe thermodynamicallythermodynamically favored form, increased as sonication time or intensity increased (Figure 88))[ [58].58]. Thus,Thus, moremore intenseintense oror extendedextended periodsperiods ofof sonicationsonication mightmight promotepromote thethe ground-stateground-state polymorphpolymorph duedue to the improved mass mass transport transport and and local local heatin heatingg from from acoustic acoustic cavitation. cavitation. Another Another example example of ofsonocrystallization sonocrystallization for for cont controllablerollable polymorphism polymorphism is isp-aminobenzoicp-aminobenzoic acid acid [44]. [44]. Rasmuson Rasmuson et et al. reportedreported thatthatp p-aminobenzoic-aminobenzoic acid acid polymorphs polymorphs were were selectively selectively crystallized crystallized by by adjusting adjusting the the degree degree of supersaturationof supersaturation and ultrasonicand ultrasonic irradiation. irradiation. Above ~25Above◦C, p~25-aminobenzoic °C, p-aminobenzoic acid is in its acidα-polymorph is in its whichα-polymorph is its energetically which is its favoredenergetically form. favored Sonocrystallization form. Sonocrystallization of p-aminobenzoic of p-aminobenzoic acid significantly acid significantly reduced the induction time, narrowed the MZW, and produced the β-polymorph above 25 °C with a low initial supersaturation.

Crystals 2018, 8, 280 7 of 20 reduced the induction time, narrowed the MZW, and produced the β-polymorph above 25 ◦C with a low initialCrystals supersaturation. 2018, 8, x FOR PEER REVIEW 7 of 20

Crystals 2018, 8, x FOR PEER REVIEW 7 of 20

Figure 8. Variation of composition of CaCO3 polymorphs under sonication (20 kHz): (a) the effect of Figure 8. Variation of composition of CaCO3 polymorphs under sonication (20 kHz): (a) the effect of intensity of ultrasound with 30 min of sonication, and (b) the effect of sonication time with 13 W/cm2 intensity of ultrasound with 30 min of sonication, and (b) the effect of sonication time with 13 W/cm 2 of sonication [58]. of sonicationFigure 8. [ 58Variation]. of composition of CaCO3 polymorphs under sonication (20 kHz): (a) the effect of intensity of ultrasound with 30 min of sonication, and (b) the effect of sonication time with 13 W/cm2 Conversely, sonocrystallization can sometimes produce a less thermodynamically stable of sonication [58]. Conversely,polymorph. Paracetamol sonocrystallization exists as either can sometimesform I (stable) produce or form aII less(metastable), thermodynamically and given the stable polymorph.differenceConversely, Paracetamol in stability sonocrystallization between exists the as forms, either can form formsometimes II has I (stable) higher produce solubility or forma less [59]. II thermodynamically (metastable), When a supersaturated and stable given the paracetamol solution was cooled without sonication, plate-like crystals (form I) were generated. differencepolymorph. in stability Paracetamol between exists the forms,as either form form II I has (stable) higher or solubilityform II (metastable), [59]. When and a supersaturatedgiven the However,difference within stability sonication, between needle-like the forms, crystals form (form II has II)higher were solubility formed (Figure [59]. When 9). The a supersaturated generation of paracetamolless stable solution forms wasfrom cooledsonocrystallization without sonication, has been plate-likereported; however, crystals until (form now, I) were no clear generated. However,paracetamol with sonication, solution was needle-like cooled without crystals sonication (form II), wereplate-like formed crystals (Figure (form9). I) The were generation generated. of less explanationsHowever, with were sonication, provided needle-like[59–64]. crystals (form II) were formed (Figure 9). The generation of stable forms from sonocrystallization has been reported; however, until now, no clear explanations less stable forms from sonocrystallization has been reported; however, until now, no clear were providedexplanations [59 were–64]. provided [59–64].

Figure 9. Optical microscopic images of paracetamol polymorphs: (a) form I produced by stirring (150 rpm), (b) form II generated via ultrasonic irradiation with 28 kHz, and (c) form II crystallized via ultrasonic irradiation with 45 kHz [59]. Figure 9. Optical microscopic images of paracetamol polymorphs: (a) form I produced by stirring Figure 9. Optical microscopic images of paracetamol polymorphs: (a) form I produced by stirring (150 rpm), (b) form II generated via ultrasonic irradiation with 28 kHz, and (c) form II crystallized via 3. Various Parameters of Sonocrystallization (150 rpm),ultrasonic (b) form irradiation II generated with 45 viakHz ultrasonic [59]. irradiation with 28 kHz, and (c) form II crystallized via ultrasonic irradiation with 45 kHz [59]. 3.1. Frequency of Ultrasound 3. Various Parameters of Sonocrystallization 3. VariousChanges Parameters in ultrasound of Sonocrystallization frequencies affect the bubble dynamics [65]. At low ultrasonic frequencies3.1. Frequency (<100 of Ultrasound kHz), cavitation bubbles experience positive and negative pressure ultrasound 3.1. FrequencywavesChanges for ofextended Ultrasound in ultrasound periods of timefrequencies because wavelengthsaffect the bubble increase dynamics as frequencies [65]. decrease.At low ultrasonicThus, the bubblefrequencies oscillation (<100 kHz),amplitude cavitation is large bubbles since experiencethe size of positive the bubble and negativediffers substantially pressure ultrasound during Changes in ultrasound frequencies affect the bubble dynamics [65]. At low ultrasonic frequencies compressionwaves for extended and expansion periods ofperiods time because [32,66]. wavelengths Conversely, increase high ultrasonic as frequencies frequencies decrease. (>200 Thus, kHz) the (<100shortenbubble kHz), the cavitationoscillation wavelength amplitude bubbles of the ultrasound experienceis large since and positive thethe lifetisizeme and of ofthe negativethe bubble cavity pressureisdiffers reduced. substantially ultrasound In all cases, during there waves for extendedarecompression generally periods denseand of time expansion clouds because of periodsca wavelengthsvitation [32,66]. bubbles, Conversely, increase and theas powerhigh frequencies ultrasonic of collapse decrease.frequencies from each Thus, (>200 bubble thekHz) is bubble oscillationdependentshorten amplitude the on wavelength their is size: large ofstronger sincethe ultrasound the for sizelarge ofand bubbles the the bubble lifeti at lowme differs offrequencies, the substantiallycavity weakeris reduced. for during smallIn all compression cases,bubbles there at and expansionhighare generallyfrequencies periods [dense32 [67,68].,66 ].clouds Conversely, While of canotvitation generally high bubbles, ultrasonic recogn andized frequencies the in thepower literature, (>200of collapse kHz)the number from shorten each of cavitating the bubble wavelength is bubbles is not controllable, and so it is exceedingly difficult to compare different frequencies due to of thedependent ultrasound on and their the size: lifetime stronger of thefor cavitylarge bubbles is reduced. at low In frequencies, all cases, thereweaker are for generally small bubbles dense at clouds changeshigh frequencies in the number [67,68]. of Whilecavitating not generallybubbles, whic recognh areized highly in the dependent literature, onthe the number specific of apparatuscavitating of cavitationused. bubbles, and the power of collapse from each bubble is dependent on their size: stronger for largebubbles bubbles is not at controllable low frequencies,, and so it weaker is exceedingly for small difficult bubbles to compare at high different frequencies frequencies [67,68 ].due While to not changes in the number of cavitating bubbles, which are highly dependent on the specific apparatus generally recognized in the literature, the number of cavitating bubbles is not controllable, and so it used.

Crystals 2018, 8, 280 8 of 20 is exceedingly difficult to compare different frequencies due to changes in the number of cavitating bubbles,Crystals which 2018,are 8, x FOR highly PEER dependent REVIEW on the specific apparatus used. 8 of 20 Koda et al. produced liposomes under ultrasonic irradiation and assessed the effects of irradiation CrystalsKoda 2018, 8et, x FORal. producedPEER REVIEW liposomes under ultrasonic irradiation and assessed the effects8 of 20of frequency on their size. Three different frequencies (43, 143, and 480 kHz) were applied at a fixed irradiation frequency2 on their size. Three different frequencies (43, 143, and 480 kHz) were applied intensityat a (8 fixedKoda W/cm intensityet al.). Itproduced was(8 W/cm observed 2).liposomes It was that observed under the size thatultrason of the the sizeic liposomes irradiation of the liposomes decreased and assessed decreased as thethe as sonic effects the sonic frequency of decreased,irradiationfrequency due to decreased,frequency changes dueon in their bubbleto changes size. dynamics Three in bubble differen (Figure dynamicst frequencies 10 )[(Figure69]. (43, 10) 143, [69]. and 480 kHz) were applied at a fixed intensity (8 W/cm2). It was observed that the size of the liposomes decreased as the sonic frequency decreased, due to changes in bubble dynamics (Figure 10) [69].

Figure 10. The effect of frequency of ultrasound on crystal size of liposomes. The ultrasonic power Figure 10. The effect of frequency of ultrasound on crystal size of liposomes. The ultrasonic power was 8 W/cm2, and the frequencies were 43 kHz (○), 133 kHz (□), and 480 kHz (◊) [69]. 2 was 8 W/cmFigure 10., and The theeffect frequencies of frequency were of ultrasound 43 kHz ( on), 133crystal kHz size ( of), liposomes. and 480 kHz The (♦ultrasonic)[69]. power wasAnother 8 W/cm study2, and investigated the frequencies the were effects 43 kHz of the (○# ),fr 133equency kHz (□ of), andultrasound 480 kHz (waves◊) [69]. on the MZW [70]. AnotherCooling studycrystallization investigated of paracetamol the effects was of tested the frequencywithout or with of ultrasound ultrasonic irradiation waves on at the multiple MZW [70]. Another study investigated the effects of the frequency of ultrasound waves on the MZW [70]. Coolingfrequencies crystallization (from 41 of to paracetamol 1140 kHz), wasand the tested MZW without was calculated or with ultrasonicas the difference irradiation between at multiplethe Cooling crystallization of paracetamol was tested without or with ultrasonic irradiation at multiple frequenciesnucleation (from temperature 41 to 1140 and kHz), the saturation and the MZWtemperature. was calculatedWhen the frequency as the difference of the ultrasound between the frequenciesincreased, the (from MZW 41 decreased to 1140 kHz), (Figure and 11). the MZW was calculated as the difference between the nucleationnucleation temperature temperature and and the the saturation saturation temperature.temperature. When When the the frequency frequency of the of ultrasound the ultrasound increased,increased, the MZW the MZW decreased decreased (Figure (Figure 11 11).).

Figure 11. The effect of ultrasound frequency on reduction of the MZW of paracetamol. The amount of reduced MZW is the difference of MZW of cooling crystallization of paracetamol without and Figure 11. The effect of ultrasound2 frequency on reduction of the MZW of paracetamol. The amount Figurewith 11. Thesonication effect of(8 ultrasoundW/cm ). The frequencycooling crystallization on reduction and of co theoling MZW sonocrystallization of paracetamol. experiments The amount of ofwere reduced performed MZW at is least the threedifference times offor MZW each freqof couency.oling Thecrystallization dots are the of average paracetamol reduction without of MZW and reduced MZW is the difference of MZW of cooling crystallization of paracetamol without and with with sonication (8 W/cm2). The cooling crystallization and cooling sonocrystallization experiments and the error bars2 are the standard deviations [70]. sonicationwere (8performed W/cm ).at Theleast coolingthree times crystallization for each frequency. and cooling The dots sonocrystallization are the average reduction experiments of MZW were performed3.2. Intensityand the at error least of Ultrasound bars three are times the standard for each deviations frequency. [70]. The dots are the average reduction of MZW and the error bars are the standard deviations [70]. 3.2. IntensityWhen ultrasoundof Ultrasound intensities increase, the size of generated crystals decreases. Increased sonication intensities cause more vigorous microscale mixing and turbulence, which causes solutes 3.2. Intensity of Ultrasound to diffuseWhen more ultrasound rapidly intensities[71]. Due toincrease, the accelerate the sized diffusion of generated of the solute,crystals the decreases. induction Increased time and Whensonication ultrasound intensities intensities cause more increase, vigorous the microscale size of generated mixing and crystals turbulence, decreases. which Increased causes solutes sonication to diffuse more rapidly [71]. Due to the accelerated diffusion of the solute, the induction time and intensities cause more vigorous microscale mixing and turbulence, which causes solutes to diffuse

Crystals 2018, 8, x FOR PEER REVIEW 9 of 20 Crystals 2018, 8, 280 9 of 20 MZW are reduced and the nucleation rate increases. Also, the vigorous microscale mixing and turbulence helps to prevent crystals from agglomerating [72]. The effect of ultrasound intensity was more rapidly [71]. Due to the accelerated diffusion of the solute, the induction time and MZW are investigatedCrystals 2018 during, 8, x FOR sonocrystallization PEER REVIEW of roxithromycin [73]. The intensity was adjusted9 offrom 20 5 to reduced and the nucleation rate increases. Also, the vigorous microscale mixing and turbulence helps 15 W/cm2, which caused the average crystal length to decrease from ~60 μm to ~15 μm during 10 to preventMZW crystals are reduced from and agglomerating the nucleation [72 ].rate The increases. effect of Also, ultrasound the vigorous intensity microscale was investigated mixing and during min sonications. sonocrystallizationturbulence helps of toroxithromycin prevent crystals [from73]. agglomerating The intensity [72]. was The adjusted effect of fromultrasound 5 to 15intensity W/cm was2, which causedinvestigated the average during crystal sonocrystallization length to decrease of roxithromycin from ~60 µ m[73]. to The ~15 intensityµm during was 10adjusted min sonications. from 5 to 3.3. Sonication15 W/cm 2Time, which caused the average crystal length to decrease from ~60 μm to ~15 μm during 10 min sonications. 3.3. SonicationAs sonication Time time increases, crystal sizes decrease and become more uniform. For short sonicationAs3.3. sonication Sonication times, solutionTime time increases, and precipitants crystal sizes are decrease not mixed and become uniformly more [32]. uniform. The Forgenerated short sonication crystals from the solution are irregularly shaped and of various sizes. Thus, prolonged sonication time times, solutionAs sonication and precipitants time increases, are not crystal mixed sizes uniformly decrease [32 ].and The become generated more crystals uniform. from For theshort solution improvesare irregularlysonication mixing shapedtimes, and solutionprevents and of and various crystals precipitants sizes. from Thus, areaggr notegating prolonged mixed [74,75].uniformly sonication Kougoulos [32]. timeThe generatedet improves al. investigated crystals mixing andthe effectspreventsfrom of crystalssonication the solution from duration are aggregating irregularly on crystal [shaped74, 75size]. and Kougoulosusing of variousadipic et acidsizes. al. investigatedand Thus, found prolonged a thesignificant effectssonication ofdifference sonicationtime in crystaldurationimproves size on crystalaccording mixing size and to using preventswhether adipic crystals sonication acid from and foundaggrwasegating applied a significant [74,75]. or notKougoulos difference (Figure et in al.12) crystal investigated [76]. sizeFurthermore, according the crystalto whethereffects size sonicationofwas sonication reduced was duration as applied sonication on crystal or not durationsize (Figure using inadipic12creased.)[76 acid]. Furthermore, andAs foundwe will a significant see, crystal this sizedifference is often was reduced indue to crystal size according to whether sonication was applied or not (Figure 12) [76]. Furthermore, sonofragmentationas sonication duration of the increased. crystals formed. As we will see, this is often due to sonofragmentation of the crystal size was reduced as sonication duration increased. As we will see, this is often due to crystalssonofragmentation formed. of the crystals formed.

Figure 12. Effect of sonication time on particle size and size distribution of adipic acid. For Figure 12.12. EffectEffect of of sonication sonication time time on particleon particle size andsize size and distribution size distribution of adipic of acid. adipic For sonicationacid. For sonication experiments, the adipic acid solution was sonicated at 20 kHz and 8.5 W/cm2. For the sonicationexperiments, experiments, the adipic the acid adipic solution acid was solution sonicated was sonicated at 20 kHz at and 20 kHz 8.5 W/cm and 8.52. W/cm For the2. For control the control experiment, stirring was performed with a magnetic stirring bar (200 rpm) [76]. controlexperiment, experiment, stirring stirring was performed was performed with a magneticwith a magnetic stirring stirring bar (200 bar rpm) (200 [76 rpm)]. [76]. 3.4. Types of Ultrasound Generator and Configurations for Sonocrystallization 3.4. Types Types of Ultrasound Generator andand ConfigurationsConfigurations for Sonocrystallization Multiple types of ultrasonic generators exist and provide many different experimental Multipleconfigurations types for of sonocrystallization. ultrasonic generators Ultrasound ex exist istgenerators and provide are typically many ultrasonic different baths, experimental horns, configurationsconfigurationsand plate transducersfor for sonocrystallization. (Figure 13). Ultrasound Ultrasound generators generators are are typically typically ultrasonic ultrasonic baths, baths, horns, horns, and plate transducers (Figure 13).13).

Figure 13. Different types of ultrasound generators: (a) ultrasonic bath [77], (b) ultrasonic horn [78], and (c) ultrasonic plate transducer [79]. Figure 13. Different types of ultrasound generators: ( (aa)) ultrasonic ultrasonic bath bath [77], [77], ( (bb)) ultrasonic ultrasonic horn horn [78], [78], and ( c)) ultrasonic ultrasonic plate transducer [79]. [79].

Crystals 2018, 8, 280 10 of 20 Crystals 2018, 8, x FOR PEER REVIEW 10 of 20

Sonicating bathsbaths are are standard standard laboratory laboratory equipment equipment and are and typically are typically used to disperseused to particles disperse in liquid.particles Such in liquid. sonicators Such sonicators are easily are accessed, easily accessed, but are only but are available only available in batch in configurations batch configurations [80,81]. Ultrasonic[80,81]. Ultrasonic horns are horns also usedare also to perform used to sonocrystallization perform sonocrystallization and offer batch and oroffer flow-through batch or configurationsflow-through configurations [45,71,82–86]. [45,71,82–86]. Scale-up to Scale-up large tubularto large flow-throughtubular flow-through reactors reactors has also has been also commercialized,been commercialized, as shown as shown in in Figure Figure 14 14[ 29[29].]. Another Another type type of ultrasound of ultrasound generator generator is the is plate the platetransducer, transducer, which which generates generates a wide a wide range range of oful ultrasoundtrasound frequencies. frequencies. It Itis is essential essential for sonocrystallization when high frequencies (>100 kH kHz)z) are required [[87].87]. With the ultrasonic plate transducer, aa batchbatch configurationconfiguration isis typicallytypically usedused forfor crystallization.crystallization.

Figure 14. Large-scale tubular flow-through ultrasonic reactors have been in use commercially. (a) Figure 14. Large-scale tubular flow-through ultrasonic reactors have been in use commercially. Schematic of the design of a flow reactor and (b) photograph of a 20-L flow cell with 40 bonded (a) Schematic of the design of a flow reactor and (b) photograph of a 20-L flow cell with 40 bonded 3 transducers from C3 Technology [[29].29].

4. Ultrasound in Slurries, Inter-Particle Collisions, Shockwaves, and Sonofragmentation 4. Ultrasound in Slurries, Inter-Particle Collisions, Shockwaves, and Sonofragmentation In a liquid–solid mixture, acoustic cavitation causes various physical phenomena. If a bubble In a liquid–solid mixture, acoustic cavitation causes various physical phenomena. If a bubble grows near a solid particle larger than the resonant size of the bubble, the bubble is deformed due grows near a solid particle larger than the resonant size of the bubble, the bubble is deformed due to the asymmetric environment [1,6]. This asymmetry causes the bubble to collapse asymmetrically, to the asymmetric environment [1,6]. This asymmetry causes the bubble to collapse asymmetrically, and a fast-moving stream of liquid (i.e., a microjet) is formed [13,14]. The microjet moves toward and a fast-moving stream of liquid (i.e., a microjet) is formed [13,14]. The microjet moves toward the solid particles and causes surface deformation or changes in the chemical composition of the the solid particles and causes surface deformation or changes in the chemical composition of the surface [1,15]. surface [1,15]. When solid particles in the mixture are smaller than the resonant size of the bubble, the When solid particles in the mixture are smaller than the resonant size of the bubble, the shockwave shockwave that is generated by acoustic cavitation causes interparticle collisions [17,18,88]. Also, that is generated by acoustic cavitation causes interparticle collisions [17,18,88]. Also, shockwaves shockwaves interact directly with solid particles, causing sonofragmentation [19,89,90]. Interparticle interact directly with solid particles, causing sonofragmentation [19,89,90]. Interparticle collisions and collisions and sonofragmentation affect the average particle size and size distribution, both by sonofragmentation affect the average particle size and size distribution, both by reducing the size of reducing the size of existing crystals and by creating secondary nucleation sites [91]. existing crystals and by creating secondary nucleation sites [91]. The effect of the shockwaves generated by acoustic cavitation in liquid–solid systems depends The effect of the shockwaves generated by acoustic cavitation in liquid–solid systems depends on the properties of the solids in the system, most notably their malleability versus their friability on the properties of the solids in the system, most notably their malleability versus their friability (brittleness) [16]. For malleable materials (e.g., metal powders), ultrasonic irradiation leads to (brittleness) [16]. For malleable materials (e.g., metal powders), ultrasonic irradiation leads to agglomeration from interparticle collisions [17,18]. The velocity of the colliding particles is sufficient agglomeration from interparticle collisions [17,18]. The velocity of the colliding particles is sufficient at the point of impact between particles to cause intense localized heating, plastic deformation, at the point of impact between particles to cause intense localized heating, plastic deformation, spot-welding, and melting (Figure 15) of various low-melting-point metals (e.g., Zn, Ni, Co, Mo). spot-welding, and melting (Figure 15) of various low-melting-point metals (e.g., Zn, Ni, Co, Mo). Very-high-melting-point metals (e.g., W), however, are not affected to the same extent, as one might Very-high-melting-point metals (e.g., W), however, are not affected to the same extent, as one might expect [18]. Similarly, there is an optimal particle size for such impacts that depends on the particle density, but is generally in the 0.5 to 50 μm range [18].

Crystals 2018, 8, 280 11 of 20 expect [18]. Similarly, there is an optimal particle size for such impacts that depends on the particle density, but is generally in the 0.5 to 50 µm range [18]. Crystals 2018, 8, x FOR PEER REVIEW 11 of 20

Crystals 2018, 8, x FOR PEER REVIEW 11 of 20

Figure 15. SEM image of zinc particles after sonication. 20 wt % of zinc slurry was sonicated by an Figure 15. SEM image of zinc particles after sonication. 20 wt % of zinc slurry was sonicated by an ultrasonic horn (20 kHz and 50 W/cm2) for 30 min. Localized melting was caused by high-velocity 2 ultrasonicFigureinterparticle horn 15. SEM (20 collisions kHzimage and ofand zinc50 particles W/cmparticles were) after for agglomerated 30sonication. min. Localized [16,17].20 wt % meltingof zinc slurry was was caused sonicated by high-velocity by an interparticleultrasonic collisions horn (20 andkHz particlesand 50 W/cm were2) for agglomerated 30 min. Localized [16,17 melting]. was caused by high-velocity interparticleSonication collisionsof molecular and particles crystals were causes agglomerated sonofragmentation [16,17]. by means of direct interactions Sonicationbetween particles of molecular and shockwaves. crystals causes Suslick sonofragmentation et al. explored the sonicati by meanson of of an direct aspirin interactions slurry under between multipleSonication experimental of molecular conditions crystals [19]. causes They sonofragmentation suggested four possibleby means mechanisms of direct interactionsof particle particles and shockwaves. Suslick et al. explored the sonication of an aspirin slurry under multiple betweenbreakage particles under sonication,and shockwaves. including Suslick interparticle et al. explored collision, the sonicatiparticle-hornon of an collision, aspirin slurryparticle-wall under experimentalmultiplecollision, conditionsexperimentaland direct [interaction19 conditions]. They between suggested [19]. They particles four suggested possibleand shockwaves four mechanisms possible (i.e., mechanisms sonofragmentation). of particle of breakage particle As under sonication,breakageshown including in under Figure sonication, interparticle 16, interparticle including collision, interparticlecollisions particle-horn rarely collision, affect collision, particle-horn particle particle-wall breakage. collision, collision, Additionally,particle-wall and direct interactioncollision,particle-horn between and anddirect particles particle-wall interaction and collisionsbetween shockwaves wereparticles negligible (i.e., and sonofragmentation). shockwaves contributors (i.e., to fragmentation.sonofragmentation). As shown Thus, in Figure Asthe 16, interparticleshownauthors collisionsinconcluded Figure that rarely16, directinterparticle affect interactions particle collisions between breakage. rarely particles Additionally, affect and particleshockwaves particle-horn breakage. were the Additionally, andmain particle-wall causes particle-horn and particle-wall collisions were negligible contributors to fragmentation. Thus, the collisionsof fragmentation. were negligible contributors to fragmentation. Thus, the authors concluded that direct authors concluded that direct interactions between particles and shockwaves were the main causes interactionsof fragmentation. between particles and shockwaves were the main causes of fragmentation. ) 3 50,000 Unbroken particles ) 3 50,000 Unbroken particles 40,000

40,000 30,000

30,000 20,000

20,000 10,000

Average Volume per Particle (μm Volume Average 10,000 0 0.00 0.02 0.04 0.06 0.08 0.10 0.12 0.14 Average Volume per Particle (μm Volume Average 0 Mass Loading (g) 0.00 0.02 0.04 0.06 0.08 0.10 0.12 0.14 Mass Loading (g) Figure 16. Effect of quantity of particle loading on final particle size after sonication for 10 s. Ultrasound was 20 kHz and 5.5 W/cm2. All masses were dispersed in 5 mL of dodecane [19]. FigureFigure 16. Effect 16. Effect of quantity of quantity of particle of particle loading loading on final on particlefinal particle size aftersize sonicationafter sonication for 10 for s. Ultrasound10 s. was 20Ultrasound kHz and was 5.5 W/cm20 kHz 2and. All 5.5 masses W/cm2. were All masses dispersed were dispersed in 5 mL of in dodecane5 mL of dodecane [19]. [19].

Crystals 2018, 8, 280 12 of 20

Crystals 2018, 8, x FOR PEER REVIEW 12 of 20 Ionic crystals are also broken due to the direct interaction between shockwaves and crystals [92]. Suslick et al.Ionic investigated crystals are thealso mechanismbroken due to ofthe sonofragmentationdirect interaction between of shockwaves slurries of and various crystals ionic [92]. crystals Suslick et al. investigated the mechanism of sonofragmentation of slurries of various ionic crystals under multiple experimental conditions. In addition, they quantitatively studied the relationship under multiple experimental conditions. In addition, they quantitatively studied the relationship betweenbetween material material properties properties (i.e., (i.e., Vickers Vickers hardnesshardness and and Young’s Young’s modulus) modulus) and the and patterns the patternsof of sonofragmentation.sonofragmentation. There There was was strong strong correlation correlation of the the rate rate of offragmentation fragmentation with thermodynamic with thermodynamic propertiesproperties of ionic of crystals: ionic crystals: the sizethe size of fragmentedof fragmented crystals decreased decreased expone exponentiallyntially with increase with increaseof of sonicationsonication time (Figure time (Figure 17). It17). is It a is mechanochemical a mechanochemical extension extension of the of theBell-Evans-Polanyi Bell-Evans-Polanyi Principle Principle or or Hammond’s Postulate: activation energies for solid fracture correlate with binding energies of Hammond’ssolids. Postulate: activation energies for solid fracture correlate with binding energies of solids.

Figure 17. Relationship between (a) Vickers hardness (Hv) and the time necessary to halve the initial Figure 17. Relationship between (a) Vickers hardness (Hv) and the time necessary to halve the initial crystal size (τ1/2) and between (b) Young’s modulus (E) and the time necessary to halve the initial

crystal sizecrystal (τ1/2 size) and(τ1/2). betweenThe dashed ( blines) Young’s are linear modulus fits [92]. (E) and the time necessary to halve the initial crystal size (τ1/2). The dashed lines are linear fits [92]. As we have discussed, the effects of ultrasound on crystals have been heavily investigated experimentally. Mathematical simulations of the sonofragmentation process using population As webalance have models discussed, that describe the effectsthe effects of of ultrasound all physical onparameters crystals such have as solution been heavilyviscosity investigatedand experimentally.applied Mathematicalpower on the crystal simulations size distribution of the sonofragmentationhave been lacking. Braatz, process Suslick, using and population coworkers balance models thathave describerecently presented the effects detailed of allpopulation physical balance parameters models for such describing as solution the crystal viscosity breakage andthat applied power onresults the from crystal ultrasound size distribution [93]. Aspirin crystals have beendispersed lacking. in various Braatz, solvents—dodecane Suslick, and and coworkers silicone have oils of known viscosity—were subjected to ultrasound and the kinetics of the resulting recently presented detailed population balance models for describing the crystal breakage that results sonofragmentation quantitatively measured. Population balance models were developed for binary from ultrasoundbreakage events [93]. Aspirinand cavitation crystals rate proportional dispersed into variousthe applied solvents—dodecane power and exponentially and related silicone to oils of known viscosity—weresolvent viscosity. subjectedAs shown in to Figure ultrasound 18, a simple and the 2-parameter kinetics population of the resulting balance sonofragmentationmodel that quantitativelyassumes measured. binary breakage Population into equal balance fragments models was tested were against developed the experimental for binary data breakage and events and cavitationdescribes rate the proportional breakage process to accurately: the applied the influenc poweres and of sonication exponentially time, ultrasonic related intensity, to solvent and viscosity. liquid viscosity are quantitatively incorporated into this simple model. The statistical analysis As shownsupports in Figure the 18breakage, a simple model 2-parameter in which cavitation population bubbles balance cause the model aspirin that crystals assumes to break binary into breakage into equaltwo fragments equal-sized was particles. tested against the experimental data and describes the breakage process accurately: the influences of sonication time, ultrasonic intensity, and liquid viscosity are quantitatively incorporated into this simple model. The statistical analysis supports the breakage model in which cavitationCrystals bubbles 2018, 8 cause, x FOR PEER the REVIEW aspirin crystals to break into two equal-sized particles. 13 of 20

Figure 18.FigureExperimental 18. Experimental (•) and (•) and simulated simulated (—) (—) cumulativecumulative mass mass fractions fractions for trials for of trials one minute of one of minute of sonicationsonication of aspirin of aspirin crystals crystals using using silicone silicone oils oils of of differentdifferent viscosities, viscosities, as labeled as labeled [93]. [93].

5. Application Sonocrystallization generates various materials with a wide range of sizes and diverse structures. One of the fields in which sonocrystallization is used widely is to produce pharmaceutical agents (PAs), since it can control crystal sizes, distributions, and polymorphisms [25,28–30]. Reductions in PA size increase the dissolution rate and solubility, especially for nanocrystals [94–97]. Also, control of polymorphisms decreases the probability of side effects [98,99]. For PAs, control of such properties (i.e., size and polymorphism) is important because they directly affect delivery to target organs and work to treat a disease. In fact, multiple PAs, including acetylsalicylic acid, paracetamol, phenacetin, carbamazepine, etc., have been generated via sonocrystallization to decrease size and size distributions, and/or to control polymorphism (Figure 19) [59,60,70,72,100–103].

Crystals 2018, 8, x FOR PEER REVIEW 13 of 20

Figure 18. Experimental (•) and simulated (—) cumulative mass fractions for trials of one minute of Crystalssonication2018, 8, 280 of aspirin crystals using silicone oils of different viscosities, as labeled [93]. 13 of 20

5. Application 5. Application Sonocrystallization generates various materials with a wide range of sizes and diverse structures.Sonocrystallization One of the generates fields variousin which materials sonocrystallization with a wide range is used of sizes widely and diverse is to structures.produce Onepharmaceutical of the fields agents in which (PAs), sonocrystallization since it can contro is usedl crystal widely sizes, is todistributions, produce pharmaceutical and polymorphisms agents (PAs),[25,28–30]. since itReductions can control in crystal PA sizes,size increase distributions, the anddissolution polymorphisms rate and [25 solubility,,28–30]. Reductions especially in PAfor sizenanocrystals increase the[94–97]. dissolution Also, ratecontrol and of solubility, polymorphisms especially decreases for nanocrystals the probability [94–97]. Also,of side control effects of polymorphisms[98,99]. For PAs, decreasescontrol of the such probability properties of (i.e., side size effects and [ 98polymorphism),99]. For PAs, controlis important of such because properties they (i.e.,directly size affect and polymorphism) delivery to target is importantorgans and because work to they treat directly a disease. affect In deliveryfact, multiple to target PAs, organs including and workacetylsalicylic to treat a disease.acid, paracetamol, In fact, multiple phenacetin, PAs, including carbamazepine, acetylsalicylic etc., acid, have paracetamol, been generated phenacetin, via carbamazepine,sonocrystallization etc., to have decrease been generated size and viasize sonocrystallization distributions, and/or to decrease to control size polymorphism and size distributions, (Figure and/or19) [59,60,70,72,100–103]. to control polymorphism (Figure 19)[59,60,70,72,100–103].

Figure 19. Microscopic images of several pharmaceutical agents generated by sonocrystallization. Optical microscopic images of (a) acetylsalicylic acid [100] and (b) paracetamol [60]. SEM images of (c) phenacetin [72] and (d) carbamazepine [101].

Another application of sonocrystallization is for the generation of nanocrystals and nanostructures [104–110]. Qian et al. reported ultrasonic irradiation as a new method for generating zinc oxide nanocrystals [111]. The conventional method was time-consuming, taking 2 days; sonication (20 kHz), however, generated nanocrystals in 3 min. Moreover, nanocrystals were formed using ultrasonic irradiation without the addition of heptane in 25 min (Figure 20). Crystals 2018, 8, x FOR PEER REVIEW 14 of 20

Figure 19. Microscopic images of several pharmaceutical agents generated by sonocrystallization. Optical microscopic images of (a) acetylsalicylic acid [100] and (b) paracetamol [60]. SEM images of (c) phenacetin [72] and (d) carbamazepine [101].

Another application of sonocrystallization is for the generation of nanocrystals and nanostructures [104–110]. Qian et al. reported ultrasonic irradiation as a new method for generating zinc oxide nanocrystals [111]. The conventional method was time-consuming, taking 2 days; Crystalssonication2018, 8, 280 (20 kHz), however, generated nanocrystals in 3 min. Moreover, nanocrystals were14 of 20 formed using ultrasonic irradiation without the addition of heptane in 25 min (Figure 20).

Figure 20. Characterizations of zinc oxide nanocrystals produced by sonocrystallization: particle Figure 20. Characterizations of zinc oxide nanocrystals produced by sonocrystallization: particle size size distribution, electron diffraction pattern, and TEM images [111]. distribution, electron diffraction pattern, and TEM images [111]. It is possible to produce a variety of nanostructures via sonocrystallization. Li et al. produced Itnanofibers is possible and to producefibrillar networks a variety using of nanostructures ultrasonic irradiation via sonocrystallization. [112]. N-lauroyl-L-glutamic Li et al. producedacid nanofibersdi-n-butylamide and fibrillar (GP-1) networks was dissolved using in ultrasonic octanol or propylene irradiation glycol [112 at]. 120N -lauroyl-°C and quenchedL-glutamic to acid room temperature in an ultrasonic water bath (35 kHz, 1–4 W/cm2) for 0–2 min. Using sonication, di-n-butylamide (GP-1) was dissolved in octanol or propylene glycol at 120 ◦C and quenched to the product was a nanofiber network structure and without sonication, spherulitic particles were room temperature in an ultrasonic water bath (35 kHz, 1–4 W/cm2) for 0–2 min. Using sonication, formed (Figure 21). The network structure exhibited an enhanced storage modulus and gelation the productcapability was compared a nanofiber with the network spherulitic structure particles. and without sonication, spherulitic particles were formed (Figure 21). The network structure exhibited an enhanced storage modulus and gelation capabilityCrystals compared 2018, 8, x FOR with PEER the REVIEW spherulitic particles. 15 of 20

Figure 21. N-lauroyl-L-glutamic acid di-n-butylamide (GP-1) nanostructures generated without Figure 21. N-lauroyl-L-glutamic acid di-n-butylamide (GP-1) nanostructures generated without sonication or with sonication: SEM images of GP-1 (a) spherulitic structures produced without sonicationsonication or with and sonication:(b) 3D interconnected SEM images fiber network of GP-1 structures (a) spherulitic with 1 structuresmin of sonication, produced and without(c) sonicationstorage and modulus (b) 3D interconnectedof the 2 wt % GP-1/polypropyle fiber networkne structures glycol gels with formed 1 min without of sonication, ultrasound and (□) ( cand) storage moduluswith of ultrasound the 2 wt ( %■), GP-1/polypropylene respectively. Scale bars are glycol 500 nm gels [112]. formed without ultrasound () and with ultrasound (), respectively. Scale bars are 500 nm [112]. Hayward et al. reported on the generation of perylene diimide (PDI) nanowires using sonocrystallization [113]. PDI and poly(3-hexylthiophene) were dissolved in 1,2-dicholorobenzene at 120 °C and cooled to 20 °C with or without sonication. Notably, sonocrystallization produced narrower, straighter, and less agglomerated PDI nanowires than the cooling crystallization without sonication (Figure 22, left). The relatively good control of sonocrystallized nanowire sizes allowed for the preparation of smooth films (Figure 22, right).

Figure 22. (Left) SEM images of perylene diimide (PDI) nanowire produced by (a) cooling crystallization without ultrasonic irradiation and (b) sonocrystallization in the presence of ultrasound; for the sonocrystallization, the PDI solution was irradiated with 35 kHz of ultrasound for 2 h [113].

6. Conclusions Sonocrystallization is an important method for the controlled preparation of crystals with desired size and size distribution. In solutions undergoing crystallization, acoustic cavitation and its physical effects reduce the induction time and the metastable zone width and increase the nucleation rates of crystal formation. Various control variables have been modified to produce micro- and nano-crystals that are of special interest to the pharmaceutical industry due to the enhanced bioavailability associated with particle size reduction. The effect of breakage of pre-existing crystals under ultrasonic irradiation has provided useful insights into the effects of

Crystals 2018, 8, x FOR PEER REVIEW 15 of 20

Figure 21. N-lauroyl-L-glutamic acid di-n-butylamide (GP-1) nanostructures generated without sonication or with sonication: SEM images of GP-1 (a) spherulitic structures produced without sonication and (b) 3D interconnected fiber network structures with 1 min of sonication, and (c) storage modulus of the 2 wt % GP-1/polypropylene glycol gels formed without ultrasound (□) and Crystals 2018, 8, 280 15 of 20 with ultrasound (■), respectively. Scale bars are 500 nm [112].

Hayward et al.al. reported reported on on the the generation generation of of perylene perylene diimide (PDI) nanowires using sonocrystallization [113]. [113]. PDI and poly(3-hexylthiophene)poly(3-hexylthiophene) were dissolved in 1,2-dicholorobenzene1,2-dicholorobenzene at 120 ◦°CC and cooled toto 2020 ◦°CC withwith oror withoutwithout sonication.sonication. Notably, sonocrystallizationsonocrystallization produced narrower, straighter, andand lessless agglomeratedagglomerated PDI nanowires than the coolingcooling crystallization without sonication (Figure(Figure 2222,, left).left). TheThe relatively relatively good good control control of of sonocrystallized sonocrystallized nanowire nanowire sizes sizes allowed allowed for forthe the preparation preparation of smooth of smooth films films (Figure (Figure 22, right).22, right).

Figure 22. (Left)(Left) SEM SEM images images of of perylene perylene diimide diimide (PDI) (PDI) nanowire nanowire produced produced by by ( a) cooling crystallization withoutwithout ultrasonic ultrasonic irradiation irradiation and (andb) sonocrystallization (b) sonocrystallization in the presence in the ofpresence ultrasound; of ultrasound;for the sonocrystallization, for the sonocrystallization, the PDI solution the wasPDI irradiatedsolution was with irradiated 35 kHz of with ultrasound 35 kHz forof 2ultrasound h [113]. for 2 h [113]. 6. Conclusions 6. Conclusions Sonocrystallization is an important method for the controlled preparation of crystals with desired Sonocrystallization is an important method for the controlled preparation of crystals with size and size distribution. In solutions undergoing crystallization, acoustic cavitation and its physical desired size and size distribution. In solutions undergoing crystallization, acoustic cavitation and its effects reduce the induction time and the metastable zone width and increase the nucleation rates of physical effects reduce the induction time and the metastable zone width and increase the crystal formation. Various control variables have been modified to produce micro- and nano-crystals nucleation rates of crystal formation. Various control variables have been modified to produce that are of special interest to the pharmaceutical industry due to the enhanced bioavailability associated micro- and nano-crystals that are of special interest to the pharmaceutical industry due to the with particle size reduction. The effect of breakage of pre-existing crystals under ultrasonic irradiation enhanced bioavailability associated with particle size reduction. The effect of breakage of has provided useful insights into the effects of ultrasonic irradiation during sonocrystallization. pre-existing crystals under ultrasonic irradiation has provided useful insights into the effects of There have been numerous reports on empirical results from sonocrystallization. While the mechanisms of action attributed to sonocrystallization and sonofragmentation have been increasing well delineated, the relative importance of these various mechanisms (bubble interface nucleation, reduction of MZW, sonofragmentation, etc.) remains, however, an open question that will depend heavily on specific systems and configurations.

Funding: This research was supported by the US AFOSR, grant FA9550-16-1-0042. Conflicts of Interest: The authors declare no conflict of interest.

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