Chemical Engineering Journal 203 (2012) 71–80

Contents lists available at SciVerse ScienceDirect

Chemical Engineering Journal

journal homepage: www.elsevier .com/locate /cej

Interactions of phase equilibria, jet fluid dynamics and mass transfer duringsupercritical antisolvent micronization: The influence of solvents

I. De Marco a, O. Knauer b, F. Cice a, A. Braeuer b,⇑, E. Reverchon a,⇑a Department of Industrial Engineering, University of Salerno, Via Ponte Don Melillo 1, 84084 Fisciano, Salerno, Italyb Lehrstuhl für Technische Thermodynamik, Erlangen Graduate School in Advanced Optical Technologies (SAOT), Universität Erlangen-Nürnberg, Paul-Gordan-Straße 6,91052 Erlangen, Germany

h i g h l i g h t s

" Observation of jet behavior in the supercritical antisolvent process." Elastic light scattering technique used to visualize different mixing behaviors depending on the kind of solvent." Interpretation of the difficulty of produce particular morphologies using some solvents.

a r t i c l e i n f o

Article history:Received 3 April 2012Received in revised form 19 June 2012Accepted 29 June 2012Available online 6 July 2012

Keywords:Supercritical antisolvent processElastic light scatteringPhase behaviorMixing behaviorParticle nucleationMicronization

1385-8947/$ - see front matter � 2012 Elsevier B.V. Ahttp://dx.doi.org/10.1016/j.cej.2012.06.129

⇑ Corresponding authors. Fax: +49 9131 85 2585964057 (E. Reverchon).

E-mail addresses: andreas.braeuer@aot.uni-erlangenunisa.it (E. Reverchon).

a b s t r a c t

This work reports the mixing behavior of some organic solvents, used for the supercritical antisolventtechnology (SAS), when they are injected into supercritical carbon dioxide. Different mixing characteris-tics can condition the morphology of the particles produced during the precipitation process. The results,obtained using an elastic light scattering technique, show, that for chloroform and acetone, there is sharptransition from two-phase mixing to single phase jet mixing at pressures larger than the mixture criticalpressure of the binary system solvent–carbon dioxide. N-methyl-2-pyrrolidone, ethanol and dimethyl-sulfoxide show a large transition range between the two-phase mixing regime below the mixture criticalpressure and the completely developed one-phase mixing regime above the mixture critical pressure. Thetransition may cover a pressure range of up to 6 MPa. Mixtures of acetone and dimethylsulfoxide show amixing behavior that is intermediate between the one of the two pure solvents. The influence of anincrease of temperature on the mixing behavior was analyzed for dimethylsulfoxide only; the transitionrange moved to higher pressures according to the corresponding shift of the mixture critical pressure ofthe binary system with temperature. A practical indication is, that it is very difficult or even impossible toproduce spherical microparticles by SAS, if solvents with a sharp transition between the two-phase andthe one-phase mixing regime are used.

� 2012 Elsevier B.V. All rights reserved.

1. Introduction

Supercritical antisolvent (SAS) precipitation has been success-fully used to micronize many compounds belonging to differentcategories, such as pharmaceuticals, superconductors, coloringmatters, explosives, polymers and biopolymers [1–4]. To describethe SAS process, three aspects and their interactions have to beconsidered, which are:

1. the fluid dynamics of the injected solution in contact withsupercritical carbon dioxide (scCO2);

ll rights reserved.

1 (A. Braeuer), fax: +39 89

.de (A. Braeuer), ereverchon@

2. high pressure vapor liquid equilibria (VLEs) of the systemformed by solute, solvent and antisolvent;

3. mass transfer to and from the injected solution, that causes thegeneration of the solute particles.

From a fluid dynamic point of view, some authors studied thebehavior of the solution injected into pressurized CO2 [5–8]. Lengs-feld et al. [5] classified the mixing mechanism as ‘‘gas-like’’ whencompletely miscible conditions were realized in the SAS precipita-tor. This behavior is attributed to the rapid disappearance of theinterfacial tension between the injected solution and the bulkCO2 phase at supercritical conditions. Dukhin et al. [6] introducedtwo characteristic times and their competition to describe theappearance of one-phase or multi-phase mixing after jet break-up. One is the jet break-up time sjb that quantifies time between

72 I. De Marco et al. / Chemical Engineering Journal 203 (2012) 71–80

the nozzle exit and the location of jet break-up; the other timescale is the interfacial tension degradation time si, quantifyingthe time required to degrade the interfacial tension between theinjected solution and the bulk CO2. If sjb < si, the interface betweenthe liquid and the fluid phase disintegrates the liquid jet in drop-lets after jet break-up. On the contrary, if sjb > si, the interfacial ten-sion has degraded to zero before the jet break-up time and gas-likemixing is obtained.

Other considerations are related to high-pressure phase equi-libria. If the solute is practically not soluble in the mixture of sol-vent and antisolvent, the VLEs of the binary solvent–antisolventsystem can replace the ternary system analysis. Consequently,based on isothermal p–x diagrams, Reverchon et al. [9–11] corre-lated three different particle morphologies to the position of theSAS operating point relative to the binary mixture critical point(MCP).

The third aspect governing the SAS process is the mass transferof the three components involved in a typical SAS experiment [12–16]. As long as an interface exists between the injected solutionand scCO2, mass transport takes place across a phase boundary.Once the interface between injected solution and bulk CO2 hasvanished, mass transport takes place according to convection anddiffusion driven ‘‘gas-like’’ mixing mechanisms.

The mutual interaction of fluid dynamics, vapor liquid equilibria(VLEs) and mass transport and their influence on nucleation andgrowth mechanisms involved in the SAS process have been in somecases investigated [4,9–11,15,17–20].

Elastic [18] and inelastic [20] in situ light scattering techniqueshave been used successfully to gain direct information about themechanisms involved in the SAS technology. Reverchon et al. [18]optically analyzed the behavior of dimethylsulfoxide (DMSO) andacetone jets in contact with CO2 at different pressures, flow rates,and nozzle diameters. The results obtained, were correlated withthe two previously mentioned time scales si and sjb and were ableto explain the occurrence of typically produced particle morpholo-gies. Marra et al. [21] recently modeled the competition betweenSAS characteristic times, elucidating the time evolution of theseprocesses. In another study [20], elastic and inelastic (Raman) lightscattering techniques were used simultaneously to explore the ef-fect of the solute concentration on the SAS process. Consequentlythe time scale model has been extended for a third characteristictime, which is the precipitation time sp quantifying the residencetime of an injected fluid element between the nozzle exit and thetime when first particles can be observed inside this fluid element.

The complete sequence of morphologies of amorphous particles(expanded microparticles, microparticles and nanoparticles) hasbeen observed only using DMSO as liquid solvent; whereas, if otherorganic solvents were used (such as ethanol or acetone) only somemorphologies have been observed [4]. For example, sphericalmicroparticles have been rarely produced using solvents differentfrom DMSO and N-methyl-2-pyrrolidone (NMP).

Nevertheless the influence of SAS parameters on morphology,particle size (PS) and particle size distribution (PSD) has beenextensively studied [22–27], the influence of the liquid solventon the evolution of the SAS process has never been studied explic-itly, though some ideas based on preliminary observations havebeen proposed [18,20].

Thus, the aim of this work is to study the influence of the kind ofsolvent on the SAS processing and the resulting particles morphol-ogy. This should be done by systematically studying the concurringtime scales of jet break-up sjb and interfacial tension degradationsi, applying an elastic light scattering technique to jets of differentsolvents at varying pressure and temperature. The solvents ana-lyzed are N-methyl-2-pyrrolidone, ethanol and chloroform. Ace-tone/DMSO mixtures have also been tested to evaluate theirinteractions during single phase/two phase mixing transition.

2. Materials and procedures

2.1. Materials

Dimethylsulfoxide (DMSO, purity 99.5%), N-methyl-2-pyrroli-done (NMP, purity 99.0%), ethanol (EtOH, purity 99.8%), acetone(AC, purity 99.8%), chloroform (CHF, purity 99.5%), and Celluloseacetate (degree of substitution = 2.5, MW � 50000), were suppliedby Sigma–Aldrich (Italy). Amoxicillin trihydrate (C16H19N3O5S3H2O; MW = 419.45) has been kindly supplied by Virbac S.A.(France). Carbon dioxide (CO2, purity 99%) was purchased fromSON (Italy). All the products were used as received.

2.2. SAS experimental setup

A schematic representation of the SAS laboratory plant used forthe experiments described in this work is reported in Fig. 1. A HPLCpump (Gilson, mod. 305) was used to deliver the liquid solvent. Adiaphragm high-pressure pump (Milton Roy, mod. Milroyal B)was used to deliver the CO2. A cylindrical vessel (V = 375 cm3),equipped with two quartz windows put along all the longitudinalsection, was used as SAS vessel. Pressure was measured with a dig-ital gauge manometer (Parker, USA) with an accuracy of 0.1 MPa.Temperature inside the precipitator is measured by a K-type ther-mocouple with an accuracy of 0.1 �C and controlled by a PID con-troller (Watlow, USA). Temperature uniformity inside the vessel isguaranteed by the presence of 16 cartridge heaters distributed inthe upper and lower part of the walls of the precipitation chamber.

The liquid mixture was delivered to the SAS vessel through athin wall nozzle with a diameter of 80 lm. A second collectionchamber located downstream the precipitator and operated atabout 2 MPa, was used to recover the liquid solvent. Further infor-mation on the SAS plant used for this experimentation is given else-where [22].

2.3. SAS procedure

A SAS experiment usually begins delivering CO2 to the SAS ves-sel until the desired pressure is reached. When antisolvent steadyflow is established, pure solvent is sent through the nozzle to thechamber for at least 15 min. When a quasi-steady state composi-tion of solvent and antisolvent is realized inside the SAS vessel,the flow of the pure solvent is stopped and the liquid solution isdelivered through the nozzle, producing the precipitation of thesolute.

At the end of the solution delivery, supercritical CO2 continuesto flow, to wash the chamber, eliminating the solution formed bythe liquid solubilized in the supercritical antisolvent. If the finalpurge with pure CO2 is not performed, the solvent contained inthe fluid phase condenses during the depressurization step andcan solubilize or modify the precipitates. At the end of the washingstep, CO2 flow is stopped and the precipitator is depressurizeddown to atmospheric pressure.

2.4. SEM analysis

Samples of the precipitated powder were collected at differentpoints inside the precipitation chamber and examined using a FieldEmission Scanning Electron Microscope (FESEM, mod. LEO 1525,Carl Zeiss SMT AG, Oberkochen, Germany). FESEM samples werecovered with 250 A of gold using a sputter coater (Agar, mod.108A). Particle size (PS) and particle size distribution (PSD) weremeasured using an image processing software (Sigma Scan Pro,Jandel Scientific) that counts, measures, and analyzes digital

PI TI

PITI

TI

TI

TC

TC

TC

TCP1

P2

S1

S2

RB

PC

MV

LS BPV

R

DM

M

M

TCTC

TCTC

Mi

LS

LDM CCD

Fig. 1. Schematic representation of the SAS apparatus with the elastic light scattering setup. S1: CO2 supply; S2: organic solvent supply; RB: refrigerating bath; P1, P2: pumps;TC: thermocouple; M: manometer; PC: precipitation chamber; MV: micrometering valve; LS: liquid separator; BPV: back pressure valve; R: rotameter; DM: dry test meter;CCD: charged-coupled device camera; LDM: long distance microscope; LS: light source; Mi: mirror.

I. De Marco et al. / Chemical Engineering Journal 203 (2012) 71–80 73

images. About 200–300 particles, coming from different images,were considered for each PSD calculation.

2.5. Light scattering setup

A light scattering setup was used to investigate the penetrationbehavior of the injected solvent and the evolution of the interfacialtension between the injected solvent and the bulk CO2; it was cou-pled to the SAS apparatus as schematized in the right part of Fig. 1.The solvent jet was illuminated by a high power white light sourcefrom a certain angle from below via a mirror. A long distancemicroscope was used to image the jet on the camera by detectingthe light scattered elastically in backward direction. The exposuretime of the camera had to be set below 50 ls to acquire sharpimages. Longer exposure times are too long to freeze the turbulentmotion of the jet and consequently result in smeared images. Tocompensate the low signal levels detectable during exposure timesshorter than 50 ls, 4 pixels of the camera chip were binned to-gether to one superpixel (two in horizontal direction and two invertical direction). After binning, the camera chip of 1376 (vertical)times 1056 (horizontal) single pixels can be considered to be com-posed of 688 (vertical) times 528 (horizontal) pixels. With the longdistance microscope 25 cm away from the jet center axis, anapproximately 1.7 mm wide and 2.3 mm high section of the jetcenter plane directly below the nozzle exit could be observed. Con-sequently, an area of 3.3 times 3.3 lm2 is imaged onto one binnedsuperpixel. Summarizing all these measures allowed the detectionof reliable signal levels at sufficiently short exposure times with astill sufficiently high local resolution.

Light can be elastically scattered away from its incident path ifit interacts with a phase boundary, with inhomogeneities, or withmatter in general. In terms of light scattering, ‘‘elastic’’ means that

the wavelength of the scattered light is equal to the wavelength ofthe incident light. There are nine different elastic light scatteringmechanisms that are strongly related to the dimensions of thematter from which the light is scattered away from its originalpath and on the wavelength of the incident light, e.g., Rayleigh-,Mie- and optical scattering. In this manuscript light scattering fromphase boundaries is termed Mie scattering (irrespective of thephase boundaries dimension) and light scattering from inhomoge-neities is termed Rayleigh scattering. Refractive index inhomoge-neities are caused by composition and density inhomogeneities.Pronounced density changes due to composition changes areknown especially for the mixtures of CO2 and organic solvents[28–31]. Consequently, regarding the mechanisms taking place inthe SAS process, Mie scattering is due to the formation of a mul-ti-phase flow; whereas Rayleigh scattering is due to compositioninhomogeneities in a single phase flow, which cause refractive in-dex inhomogeneities.

In a previous work [18] we comprehensively illustrated and ex-plained the specific characteristics of the different involved elasticlight scattering signals originating from either large drops in caseof dripping, from tiny droplets in case of atomization and fromrefractive index gradients in case of gas-like mixing when theinterface has already vanished.

3. Results and discussion

An accurate analysis of SAS literature, reported in [11], showedthat microparticles of several compounds were prevalently ob-tained using DMSO, sometimes using dichloromethane (DCM)and DCM mixtures with a second solvent, and only in some casesusing EtOH. To understand why microparticles can be producedonly in particular conditions of pressure and temperature, jet

74 I. De Marco et al. / Chemical Engineering Journal 203 (2012) 71–80

experiments were performed to analyze fluid dynamic behavior ofseveral of the most frequently solvents used in SAS processing. Ifnot differently stated, all the jet experiments were carried out at40 �C, using an 80 lm diameter nozzle, with a liquid flow rate of2.5 mL min�1 and with a CO2 flow rate adapted to obtain a molefraction of CO2 in the precipitator of 0.99. This mole fraction valuewas fixed to assure that, independently of the pressure, the operat-ing point was located outside the miscibility hole of the binary sys-tem solvent–CO2 either in the subcritical gas phase or in thesupercritical region. The operating pressure was varied from belowthe MCP (subcritical conditions), to near above the MCP (slightlyhigher than mixture critical conditions), to far above the MCP (fulldeveloped supercritical conditions) to analyze the evolution of theinterface between the injected solvent and CO2. The solvents stud-ied are NMP, EtOH, and CHF, which extend the database of the sol-vents DMSO and AC reported in a previous work [18]. Furthermorethe evolution of the interfacial tension was analyzed for mixturesof DMSO and AC. The influence of temperature has been studiedfor pure DMSO only.

3.1. Vapor–liquid equilibria of the investigated binary mixtures andproperties of the pure solvents

The VLEs of the binary systems solvent/CO2 at 40 �C, for the sol-vents investigated in this work: CHF, EtOH, DMSO, AC and NMP,can be obtained from literature [32–35]. The two-phase regionsare similar with respect to area and the position of the mixturecritical point (MCP).

Unfortunately, though SAS has been proposed also for mixturesof solvents with CO2 [36–39], no VLE data are available in literaturefor the ternary system DMSO/AC/CO2. However, the MCP of the sin-gle solvents (DMSO, AC) in CO2 are similar; for example, at 40 �C,MCP coordinates, in terms of pressure and composition, are8.65 MPa/0.98 for DMSO [34] and 8.01 MPa/0.973 for AC [33].Therefore, we hypothesized in this work that MCPs of DMSO–ACmixtures are intermediate between the corresponding values ofthe binary systems.

For the experiments taken for pure DMSO at different tempera-tures, the pressure and composition data at the MCP were takenfrom literature [40].

Other information useful for the discussion of the experimentalresults are density, viscosity and surface tension of the solventsused in this work. These data, at a temperature of 40 �C, are re-ported in Table 1.

3.2. Comparison of the jet behavior of the solvents DMSO, NMP, CHF,EtOH, and AC at 40 �C

Fig. 2 summarizes jet images of CHF, AC, NMP, EtOH and DMSO.The SAS process conditions are the ones described at the beginningof this chapter. In the left column, typical jet images for operationpressures below the MCP are given. They clearly show that the li-quid phase is atomized into droplets after jet break-up. At theseoperating conditions, the interfacial tension degradation time si

Table 1Properties of the investigated liquid solvents at 40 �C; densities and viscosities aretaken from the Perry’s chemical engineers handbook [41] and surface tensions wereevaluated using the Parachor method [42].

Solvent Density (kg m�3) Viscosity (cP) Surface tension (N m�1)

NMP 1025 1.41 4.05 � 10�2

EtOH 772 0.81 2.03 � 10�2

CHF 1455 0.47 2.47 � 10�2

DMSO 1081 1.51 4.09 � 10�2

AC 769 0.27 1.89 � 10�2

significantly exceeds the jet break-up time sjb and, consequently,mixing takes place in a two-phase flow, where the liquid phasein form of droplets mixes with the bulk CO2 phase. The right col-umn of Fig. 2 shows typical jet images where mixing takes placein a single-phase flow. In this case the interfacial tension betweenthe injected solvent and the bulk CO2 is completely degraded at thetime of jet break-up. The pressure given for each solvent in theright column is the minimum pressure for which completely devel-oped single-phase mixing has been observed. Thus, the sequence ofsolvent images in Fig. 2 from the top to the bottom is adjusted tothe minimum pressure at which completely developed single-phase mixing was observed. The jet images in the middle columnof Fig. 2 represent operation conditions at which a two-phase mix-ing flow is observable in the center of the jet (indicated by thebright cloud at the nozzle exit) with a single-phase mixing flowin the outer mixing regions of the jet (indicated by the bright cordsat the jet edges).

In the case of CHF, no Mie scattering signals are observable inthe inner part of the jet. It means that a sharp transition from atwo-phase mixing flow to a single-phase mixing flow has been ob-served when the pressure was tuned near above the MCP. For AC,the transition from a two-phase mixing flow to a completely devel-oped single-phase mixing flow took place over a rather narrowpressure range. However, in contrast to CHF, at least one operationpressure showing this transition was identified for AC (at 8.0 MPa).In the case of DMSO the transition from two-phase to completelydeveloped single-phase mixing flow developed in the widest pres-sure range. The behavior of NMP and EtOH is intermediate be-tween the behavior of AC and DMSO. In these cases, thetransition region covers a narrower range of pressures (from 8 to10 MPa) than for DMSO (from 9 to 16 MPa).

3.3. Comparison of the jet behavior of solvent mixtures of DMSO andAC at 40 �C

Binary solvent mixtures have also been used in SAS experi-ments [36–39] to modify the precipitation morphology of somesolutes (for example, amoxicillin, ipratropium bromide, terbutalinesulfate). In this work, DMSO–AC mixtures were tested to study ifthe transition between two-phase and single-phase mixing of asolvent (AC) can be modified by the presence of a second solventwith a completely different behavior (DMSO).

Fig. 3 shows jet images of solvent mixtures of DMSO and AC intoscCO2 at the previously indicated process conditions. The order ofthe images follows the same strategy applied to the structure ofthe images reported in Fig. 2. The left column in Fig. 3 representsSAS operation pressures for which a two-phase mixing flow ispresent, as the time scale of interfacial tension vanishing si signif-icantly exceeds the jet break-up time sjb. The images in the middlecolumn represent operation pressures for which a transition fromthe two-phase to the single-phase mixing regime could be identi-fied. The right column represents a jet image of the lowest pressureat which completely developed single-phase mixing could be ob-served. Thus, comparing the images illustrated in Fig. 3 and therespective pressures, the pressure range at which the transitionfrom a two-phase to a single-phase mixing process takes place en-larges with DMSO content in the injected solvent mixture.Comparing the mixing behavior of pure AC and pure DMSO inFig. 2 with the mixing behavior of the AC-rich and the DMSO-richmixtures in Fig. 3 some differences are evident. While the pure ACjet is in the transition range at 8.5 MPa, the AC-rich mixture jet(75% AC) is still in the two-phase mixing regime at the same pres-sure. While the pure DMSO jet is in the transition range at10.0 MPa, the DMSO-rich jet (75% DMSO) is already in thecompletely developed single-phase mixing regime. However, notransition region could be found for the injection of the AC-rich sol-

Fig. 2. Jet images of CHF, AC, NMP, EtOH and DMSO injected at 40 �C with a flow rate of 2.5 mL min�1 through the Ø = 80 lm nozzle into scCO2.

I. De Marco et al. / Chemical Engineering Journal 203 (2012) 71–80 75

vent mixture; the transition, represented as a Mie scattering signalin the center of the jet, is present for 50% AC mixtures and its rangeenlarges with increasing DMSO content.

At 8.5 MPa, all solvent mixtures reveal a two-phase mixing pro-cess. Thus, the mixing behavior at low pressures is governed by thepresence of DMSO, as all solvent mixtures, independently of the

Fig. 3. Jet images of solvent mixtures of DMSO and AC injected at 40 �C with a flow rate of 2.5 mL min�1 through a Ø = 80 lm nozzle into scCO2.

Fig. 4. Jet images of DMSO injected at various temperatures and pressures into scCO2.

76 I. De Marco et al. / Chemical Engineering Journal 203 (2012) 71–80

Table 2Nozzle Reynolds and Ohnesorge numbers.

Solvent Re Oh

NMP 482 2.45 � 10�2

EtOH 626 2.31 � 10�2

CHF 2065 0.87 � 10�2

DMSO 474 2.55 � 10�2

Acetone 1903 0.78 � 10�2

Fig. 5. FESEM images of amoxicillin precipitated from NMP: (a) expanded micro-particles obtained at 8.0 MPa; (b) microparticles obtained at 10.0 MPa and (c)nanoparticles obtained at 15.0 MPa.

I. De Marco et al. / Chemical Engineering Journal 203 (2012) 71–80 77

DMSO percentage, show behavior similar to that of pure DMSO. Onthe other hand, the minimum pressure at which a complete single-phase mixing is observed is increasing from 9.0 MPa for the AC-rich mixture over 9.5 MPa for the 50/50% mixture up to 10 MPafor the DMSO-rich mixture. This indicates that the achievementof single-phase mixing and therefore the behavior at higher pres-sures is dominated by the presence of AC in the solvent mixtures.As a consequence, the pressure range at which the transition froma two-phase to a single-phase mixing process takes place decreaseswith AC content of the injected solvent mixture. This explains, whyno transition from two-phase to single-phase mixing behavior wasobserved for the AC-rich mixture. Due to the presence of DMSO,the two-phase mixing region is extended up to 8.5 MPa, whilethe high amount of AC in the solvent mixture reduces the pressurefor the onset of single-phase mixing down to 9.0 MPa. Due to thelimited accuracy of the pressure gauge, the pressure range between8.5 MPa and 9.0 MPa could not be resolved further, disabling theobservation of the transition regime. Summarizing, at lower pres-sures slightly above the MCP, the mixing behavior of the injectedsolvent mixtures is governed by DMSO. The higher the pressure,the more the mixing behavior is governed by AC.

3.4. Comparison of the jet behavior of DMSO at different temperatures

Fig. 4 shows jet images of DMSO injected at various tempera-tures and at the previously indicated process conditions into CO2.At 35 �C and 12 MPa, mixing takes place in the completely devel-oped single-phase mixing regime. At the same pressure, but at atemperature of 40 �C, mixing takes place in the transition region.This is represented by the marginally observable Mie signals inthe jet core. At the same pressure but at a higher temperature(50 �C), the mixing behavior of DMSO can clearly be assigned tothe transition range between the two-phase and the one-phasemixing flow. At 60 �C the transition is still observable at pressuresas high as 16 MPa. Comparing the experimental results with thepressures at the MCP of the binary mixtures of DMSO and CO2 ob-tained from literature [40], the results can be simply explained:since the pressure of the MCP increases with temperature, higherpressures are required to shift the mixing behavior of the injectedsolvent to the single-phase mixing regime. These results confirmthe SAS precipitation results obtained using gadolinium acetate[19] at different temperatures.

3.5. Jet behavior interpretation in terms of characteristic times

Recalling the explanation given for DMSO behavior [18], thetransition between jet break-up controlled fluid dynamics andgas mixing is governed by the competition of the two characteristictimes si and sjb. Particularly, si depends on the interfacial tensiondegradation. Atomization processes, like jet break-up, are con-trolled by cohesive and disruptive forces; particularly different sol-vents and solvent mixtures are characterized by different surfacetensions (r) and viscosities (l) that represent the cohesive forcesof the liquid to be atomized.

Looking at surface tensions of EtOH, NMP, CHF, DMSO and AC,we can observe that surface tension values for DMSO and NMPare similar (however, rDMSO > rNMP); whereas, the surface tensionfor all the other pure solvents are lower (at around 60–65% rDMSO).

Looking at solvent viscosities, we can observe that lDMSO

> lNMP > lEtOH > lCHF > lAC. Therefore, the viscosity seems to havea great influence on the kind of jet behavior. Considering that, at40 �C, CHF and AC presented sharp (rather sharp for AC) transitionsfrom two-phases to one-phase behavior, NMP presented a transi-tion up to 11 MPa, EtOH up to 12 MPa, and DMSO up to 16 MPa,these transitions approximately respect the order of solventviscosities.

78 I. De Marco et al. / Chemical Engineering Journal 203 (2012) 71–80

To take simultaneously into account the effect of different sol-vent properties, dimensionless numbers usually used in jet fluiddynamics, such as Reynolds (Re) and Ohnesorge (Oh) number, haveto be evaluated. Re number is defined as the ratio of inertial forcesto viscous forces, whereas Oh number relates the viscous forces tothe surface tension. Nozzle Re and Oh numbers for all the solventsare reported in Table 2. As a confirmation of the great influence ofsolvent viscosities on jet behavior, it is possible to observe thatReDMSO < ReNMP < ReEtOH < ReCHF < RelAC, even if solvent densitiesvariations follow a different trend. Oh numbers evaluation didnot give further information on jet behavior.

It is also relevant to remember that surface tension disappear-ance during the mixing of scCO2 with the liquid jet is a dynamicprocess that requires some time to be completed. This time wasmeasured in a previous work on laser scattering in SAS jets [20]and was successfully modeled by Marra et al. [21]. Obviously, thedegradation time depends on the starting value of the dynamicsurface tension and on the relaxation function; i.e., the larger thesurface tension of the pure liquid, the longer is the transition ofthe interfacial tension to zero. In other words, the competition be-tween si and sjb will propose si > sjb for pressures above the MCP ifthe solvents feature a higher initial surface tension. Therefore, thedifferent contribution of the two cohesive forces gives a goodexplanation of all the results obtained during this work.

3.6. SAS precipitation experiments at different pressures

Some SAS precipitation experiments were performed using ACor NMP as liquid solvents; they were selected considering thatthe corresponding liquid jets had very different behaviors, whenin contact with supercritical CO2.

To perform SAS experiments using NMP as the liquid solvent, weused amoxicillin as solute. The experiments were performed at afixed temperature and liquid solution concentration (40 �C and40 mg/mL), varying the operating pressure. We observed that, at8.0 MPa, that corresponds to a two-phase mixing region, expandedmicroparticles were obtained (Fig. 5a). Increasing the pressure to10.0 MPa, in correspondence of the transition from two-phase toone phase mixing, microparticles were obtained (Fig. 5b). A further

Fig. 6. Volumetric cumulative distributions of amoxicillin particles obtained fromNMP at different pressures. Abscissa axis: log scale before the break, linear scaleafter the break.

increase of pressure (in correspondence of one-phase mixing) led tothe production of nanoparticles, as it is possible to observe in theFESEM image reported in Fig. 5c. The volumetric cumulative parti-cle distributions for all the obtained powders are reported in Fig. 6.

The model compound used for the precipitation experiments inAC was cellulose acetate. Working at 40 �C and 15 mg/mL, we per-formed SAS precipitation experiments at increasing pressures. Inthis case, we observed that in the two-phase region (at 7.5 MPa) ex-panded microparticles were produced (Fig. 7a). Working at 8.0 MPa(in correspondence of the transition from two-phase to one-phasemixing), particles in the range 100–250 nm were obtained

Fig. 7. FESEM images of cellulose acetate precipitated from AC: (a) expandedmicroparticles obtained at 7.5 MPa; (b) nanoparticles obtained at 8.0 MPa and (c)nanoparticles obtained at 15.0 MPa.

Fig. 8. Volumetric cumulative distributions of cellulose acetate particles obtainedfrom AC at different pressures. Abscissa axis: log scale before the break, linear scaleafter the break.

I. De Marco et al. / Chemical Engineering Journal 203 (2012) 71–80 79

(Fig. 7b), whereas at 15.0 MPa nanoparticles with a lower meandiameter were obtained (Fig. 7c). The corresponding volumetriccumulative particle distributions are reported in Fig. 8. It is note-worthy that no microparticles were obtained for cellulose acetate.

4. Conclusions and perspectives

From a practical SAS operation point of view, the results ob-tained in this work mean that, when immediately above the MCPthe interfacial tension is degraded to zero (si � sjb), no transition re-gion (or a very sharp transition) between two-phase and one-phasemixing is observable. In this case, droplets are not formed in the jetor their formation is possible in a very narrow range of process con-ditions and, consequently, microparticles, that remain as a skeletonof these droplets, cannot be produced using the conventional SAStechnique. If spherical microparticles of a solute are required froma solvent that shows no transition region, this solvent should bemodified with a second one showing a broader transition range.The effective generation of spherical microparticles using solventmixtures of this kind will be demonstrated in future works.

Acknowledgments

The authors gratefully acknowledge financial support for travelto and accommodation in Salerno of Oliver Knauer and AndreasBraeuer by the German Academic Exchange Service (DAAD) inthe framework of the Vigoni program. The authors furthermoregratefully acknowledge funding of parts of this work and of theErlangen Graduate School in Advanced Optical Technologies(SAOT) by the German Research Foundation (DFG) in the frame-work of the German excellence initiative. Moreover, the authorsacknowledge Alfredo Galdieri for his help in performing the exper-iments and MiUR (Italian Ministry of Scientific Research) for thefinancial support.

References

[1] E. Reverchon, Supercritical antisolvent precipitation of micro- and nano-particles, J. Supercrit. Fluids 15 (1) (1999) 1–21.

[2] A. Shariati, C.J. Peters, Recent developments in particle design usingsupercritical fluids, Curr. Opin. Solid State Mater. Sci. 7 (4–5) (2003) 371–383.

[3] Y. Hakuta, H. Hayashi, K. Arai, Fine particle formation using supercritical fluids,Curr. Opin. Solid State Mater. Sci. 7 (4–5) (2003) 341–351.

[4] E. Reverchon, I. De Marco, Mechanisms controlling supercritical antisolventprecipitate morphology, Chem. Eng. J. 169 (2011) 358–370.

[5] C.S. Lengsfeld, J.P. Delplanque, V.H. Barocas, T.W. Randolph, Mechanismgoverning microparticle morphology during precipitation by a compressedantisolvent: atomization vs. nucleation and growth, J. Phys. Chem. B 104(2000) 2725–2735.

[6] S.S. Dukhin, Y. Shen, R. Dave, R. Pfeffer, Droplet mass transfer, intradropletnucleation and submicron particle production in two-phase flow of solvent–supercritical antisolvent emulsion, Colloids Surf., A 261 (2005) 163–176.

[7] A. Martin, M.J. Cocero, Numerical modeling of jet hydrodynamics, masstransfer, and crystallization kinetics in the supercritical antisolvent (SAS)process, J. Supercrit. Fluids 32 (2004) 203–219.

[8] T. Petit-Gas, O. Boutin, I. Raspo, E. Badens, Role of hydrodynamics insupercritical antisolvent processes, J. Supercrit. Fluids 51 (2) (2009) 248–255.

[9] E. Reverchon, I. De Marco, E. Torino, Nanoparticles production by supercriticalantisolvent precipitation: a general interpretation, J. Supercrit. Fluids 43 (1)(2007) 126–138.

[10] E. Reverchon, I. De Marco, R. Adami, G. Caputo, Expanded micro-particles bysupercritical antisolvent precipitation: interpretation of results, J. Supercrit.Fluids 44 (1) (2008) 98–108.

[11] E. Reverchon, R. Adami, G. Caputo, I. De Marco, Spherical microparticlesproduction by supercritical antisolvent precipitation: interpretation of results,J. Supercrit. Fluids 47 (1) (2008) 70–84.

[12] J.O. Werling, P.G. Debenedetti, Numerical modeling of mass transfer in thesupercritical antisolvent process, J. Supercrit. Fluids 16 (2) (1999) 167–181.

[13] J.O. Werling, P.G. Debenedetti, Numerical modeling of mass transfer in thesupercritical antisolvent process: miscible conditions, J. Supercrit. Fluids 18 (1)(2000) 11–24.

[14] A. Braeuer, R. Adami, S. Dowy, M. Rossmann, A. Leipertz, Observation of liquidsolution volume expansion during particle precipitation in the supercriticalCO2 antisolvent process, J. Supercrit. Fluids 56 (2) (2011) 121–124.

[15] F. Chavez, P.G. Debenedetti, J.J. Luo, R.N. Dave, R. Pfeffer, Estimation of thecharacteristic time scales in the supercritical antisolvent process, Ind. Eng.Chem. Res. 42 (13) (2003) 3156–3162.

[16] J. Bałdyga, D. Kubicki, B.Y. Shekunov, K.B. Smith, Mixing effects on particleformation in supercritical fluids, Chem. Eng. Res. Des. 88 (9) (2010) 1131–1141.

[17] M. Sarkari, I. Darrat, B.L. Knutson, Generation of microparticles using CO2 andCO2-philic antisolvents, AIChE J. 46 (9) (2000) 1850–1859.

[18] E. Reverchon, E. Torino, S. Dowy, A. Braeuer, A. Leipertz, Interactions of phaseequilibria, jet fluid dynamics and mass transfer during supercriticalantisolvent micronization, Chem. Eng. J. 156 (2) (2010) 446–458.

[19] I. De Marco, E. Reverchon, Influence of pressure, temperature andconcentration on the mechanisms of particle precipitation in supercriticalantisolvent micronization, J. Supercrit. Fluids 58 (2011) 295–302.

[20] A. Braeuer, S. Dowy, E. Torino, M. Rossmann, S.K. Luther, E. Schluecker, A.Leipertz, E. Reverchon, Analysis of the supercritical antisolvent mechanismsgoverning particles precipitation and morphology by in situ laser scatteringtechniques, Chem. Eng. J. 173 (2011) 258–266.

[21] F. Marra, I. De Marco, E. Reverchon, Numerical analysis of the characteristictimes controlling supercritical antisolvent micronization, Chem. Eng. Sci. 71(2012) 39–45.

[22] E. Reverchon, I. De Marco, Supercritical antisolvent micronization of cefonicid:thermodynamic interpretation of results, J. Supercrit. Fluids 31 (2) (2004) 207–215.

[23] E. Reverchon, I. De Marco, Supercritical antisolvent precipitation ofcephalosporins, Powder Technol. 164 (3) (2006) 139–146.

[24] A. Tenorio, M.D. Gordillo, C. Pereyra, E.J. Martınez de la Ossa, Controlledsubmicro particle formation of ampicillin by supercritical antisolventprecipitation, J. Supercrit. Fluids 40 (2) (2007) 308–316.

[25] M.-S. Kim, S. Lee, J.-S. Park, J.-S. Woo, S.-J. Hwang, Micronization of cilostazolusing supercritical antisolvent (SAS) process: effect of process parameters,Powder Technol. 177 (2) (2007) 64–70.

[26] I. De Marco, E. Reverchon, Supercritical antisolvent micronization ofcyclodextrins, Powder Technol. 183 (2) (2008) 239–246.

[27] M. Rossmann, A. Braeuer, S. Dowy, T. Gottfried Gallinger, A. Leipertz, E.Schluecker, Solute solubility as criterion for the appearance of amorphousparticle precipitation or crystallization in the supercritical antisolvent (SAS)process, J. Supercrit. Fluids 66 (2012) 350–358.

[28] S. Dowy, A. Braeuer, R. Schatz, E. Schluecker, A. Leipertz, CO2 partial densitydistribution during high-pressure mixing with ethanol in the supercriticalantisolvent process, J. Supercrit. Fluids 48 (2009) 195–202.

[29] A. Kordikowski, A.P. Schenk, R.M. Van Nielen, C.J. Peters, Volume expansionsand vapor–liquid equilibria of binary mixtures of a variety of polar solventsand certain near-critical solvents, J. Supercrit. Fluids 8 (1995) 205–216.

[30] Y. Sun, B.Y. Shekunov, Surface tension of ethanol in supercritical CO2, J.Supercrit. Fluids 23 (2003) 73–83.

[31] S. Dowy, A. Braeuer, K. Reinhold-Lopez, A. Leipertz, Laser analyses of mixtureformation and the influence of solute on particle precipitation in the SASprocess, J. Supercrit. Fluids 50 (2009) 265–275.

[32] A.M. Scurto, C.M. Lubbers, G. Xu, J.F. Brennecke, Experimental measurementand modeling of the vapor–liquid equilibrium of carbon dioxide + chloroform,Fluid Phase Equilib. 190 (2001) 135–147.

80 I. De Marco et al. / Chemical Engineering Journal 203 (2012) 71–80

[33] H.-Y. Chiu, M.-J. Lee, H.-M. Lin, Vapor–liquid phase boundaries of binarymixtures of carbon dioxide with ethanol and acetone, J. Chem. Eng. Data 53(2008) 2393–2402.

[34] A. Vega Gonzalez, R. Tufeu, P. Subra, High-pressure vapor�liquid equilibriumfor the binary systems carbon dioxide + dimethyl sulfoxide and carbondioxide + dichloromethane, J. Chem. Eng. Data 47 (2002) 492–495.

[35] M.J. Lazzaroni, D. Bush, J.S. Brown, C.A. Eckert, High-pressure vapor–liquidequilibria of some carbon dioxide + organic binary systems, J. Chem. Eng. Data50 (2005) 60–65.

[36] N. Elvassore, A. Bertucco, P. Caliceti, Production of protein-loaded polymericmicrocapsules by compressed CO2 in a mixed solvent, Ind. Eng. Chem. Res. 40(3) (2001) 795–800.

[37] C.G. Kalogiannis, E. Pavlidou, C.G. Panayiotou, Production of amoxicillinmicroparticles by supercritical antisolvent precipitation, Ind. Eng. Chem. Res.44 (24) (2005) 9339–9346.

[38] Y. Ho Kim, K.S. Shing, Supercritical fluid-micronized ipratropium bromide forpulmonary drug delivery, Powder Technol. 182 (1) (2008) 25–32.

[39] Y. Ho Kim, C. Sioutas, P. Fine, K.S. Shing, Effect of albumin on physicalcharacteristics of drug particles produced by supercritical fluid technology,Powder Technol. 182 (3) (2008) 354–363.

[40] H.-Y. Chiu, R.-F. Jung, M.-J. Lee, H.-M. Lin, Vapor–liquid phase equilibriumbehavior of mixtures containing supercritical carbon dioxide near criticalregion, J. Supercrit. Fluids 44 (2008) 273–278.

[41] R.H. Perry, D.W. Green, Perry’s Chemical Engineers’ Handbook, seventh ed.,2001 McGraw-Hill Professional.

[42] D.B. Macleod, On a relation between surface tension and density, Trans.Faraday Soc. 19 (1923) 38–41.