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Department of Chemical and Petroleum Engineering, University of Kansas, Lawrence, Kansas 66045 ... solution and antisolvent in the GAS and PCA process...
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MATERIALS AND INTERFACES Dense Gas Antisolvent Precipitation: A Comparative Investigation of the GAS and PCA Techniques Francesco Fusaro, Markus Ha1 nchen, and Marco Mazzotti* ETH Swiss Federal Institute of Technology Zurich, Institute of Process Engineering, Sonneggstrasse 3, CH-8092 Zurich, Switzerland

Gerhard Muhrer Chemical & Analytical Development, Novartis Pharma AG, CH-4002 Basel, Switzerland

Bala Subramaniam Department of Chemical and Petroleum Engineering, University of Kansas, Lawrence, Kansas 66045

Experimental data are reported on particle size distributions of paracetamol precipitated from an acetone solution using compressed CO2 as an antisolvent. When the solution is sprayed into dense CO2 using the “precipitation with compressed antisolvents” (PCA) process (in two different PCA units), the average particle size is approximately 2 µm in the 83-120 bar, 33-62 °C, 70138 g/min of CO2 range. When the operating pressure and temperature are below or close to the critical locus for the CO2 + acetone binary, the particles tend to be spherical and agglomerated, presumably because the surface roughening temperature was exceeded. Well above the critical locus, the particles are less aggregated with distinguishable crystal faces. In contrast, bubbling compressed CO2 through the paracetamol solution (the so-called GAS process) yielded 90-250 µm particles at 25 °C in the 5-50 g/min of CO2 range. Through the definition of characteristic mass-transfer times (τmt) for the PCA and GAS processes based on published mathematical models, it is shown that the 2 orders of magnitude disparity in the average particle size is mirrored by a similar disparity in the τmt values for the two processes. These results suggest that the PCA and GAS processes, with common underlying mass-transfer mechanisms, may be essentially viewed in a continuum of characteristic mass-transfer time scales, with the higher τmt values yielding progressively larger particles. This result may be useful to rationally interpret and manipulate particle sizes in these processes. 1. Introduction This work addresses the precipitation of pharmaceutical compounds by using compressed CO2 as an antisolvent. The main advantage of dense gas antisolvent techniques is the possibility of obtaining in one step virtually residue-free and dry products at rather mild operating temperatures, without the need for downstream processing. Further, with relatively minor variations in the operating conditions (pressure, temperature, and flow rates), the average particle size, particle size distribution (PSD), and particle morphology may be tuned to manipulate the product specifications. During the past decade, numerous dense gas assisted particle formation processes have been proposed, among which the processes using compressed gas antisolvents are generally considered the most promising.1-5 Such processes, in general, fall under two types. In gas antisolvent precipitation (GAS), a vessel containing the * To whom correspondence should be addressed. Tel.: +41-1-6322456. Fax: +41-1-6321141. E-mail: mazzotti@ ipe.mavt.ethz.ch.

starting solution is pressurized by CO2, causing a volumetric expansion of the liquid phase and precipitation.6 In the precipitation with compressed antisolvent (PCA) process, the liquid solution is sprayed through a nozzle into a vessel initially pressurized with the dense gas. The PCA technique provides more efficient mass transfer between the antisolvent and solution and is thus particularly suitable for systems where high supersaturation and fast precipitation are desirable. The mass-transfer efficiency can be further enhanced by either adjusting the operating parameters to achieve full miscibility between the solvent and antisolvent or substituting capillary nozzles by more sophisticated devices, such as ultrasonic dispersion devices, coaxial nozzles, or two-component jets. The nozzles allow intimate contact between the solution and antisolvent prior to the entrance of the precipitator.7-9 Given the starkly different modes of contacting the solution and antisolvent in the GAS and PCA processes, it is of interest to understand any differences in the characteristics of the particles formed by the two processes. Surprisingly, only one such comparative study was found in the literature. The precipitation of

10.1021/ie049495h CCC: $30.25 © 2005 American Chemical Society Published on Web 01/27/2005

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Figure 1. PCA setup at Novartis Pharma AG (unit 1). Details are provided in the text.

copper indomethacin using GAS and PCA processes has been investigated experimentally, and a qualitative comparison of the two processes has been presented.10 The lack of systematic investigations is the motivation for the present study aimed at a better understanding of the relationships between operating conditions and product quality in the GAS and PCA processes. Our group has recently investigated the effect of the GAS operating conditions on the product quality of three different pharmaceutical compounds, and different patterns of behavior were observed. In one example, the CO2 addition rate was varied, causing the average particle size of a proprietary pharmaceutical intermediate to vary between 300 nm and 10 µm.11,12 In a second example, paracetamol was precipitated from acetone, and again the average particle size could be tuned between 90 and 250 µm by changing the CO2 addition rate.13 In sharp contrast, virtually no effect was observed during the precipitation of lysozyme from dimethyl sulfoxide (DMSO).14 These observations were explained using a population balance model of the GAS process, which accounts for primary and secondary nucleation as well as growth.15 All patterns of behavior observed experimentally could be obtained by adjusting the relative weighting factors of the primary and secondary nucleation steps. Specifically, it was shown that the CO2 addition rate allows control of the average particle size and the PSD of the final product when primary nucleation is dominant. In contrast, when secondary nucleation dominates, the average particle size of the product remains mostly unaffected by changes in the CO2 addition rate. In this work, we compare GAS and PCA processes applied to the recrystallization of paracetamol from an acetone solution. First, we present the PCA experimental results in terms of the operating parameters, i.e., pressure and temperature. The experiments were carried out in two different setups, thus enabling us to assess process robustness. The results from the two techniques are interpreted with a mathematical model, showing that, at least for the specific system considered,

the PCA process may be viewed as an extension of the GAS process. 2. Experimental Section 2.1. Experimental Setup. PCA experiments were carried out in two different units located at Novartis Pharma AG (unit 1) and at the University of Kansas (unit 2). The standard experimental arrangement used for PCA experiments in unit 1 is shown in Figure 1. Liquid CO2 is drawn from a dip-tube cylinder, subcooled in a cryostat (Cr1, TIC1), and delivered at constant mass flow rate (P1, FIC1). Prior to entering the nozzle (N), CO2 is brought to the operating temperature in a coil immersed in a heated water bath. A two-component nozzle (two-component jet) (Schlick 970-S8; 0.3 mm) was used in the experiments and fitted onto the top of a 1 L stainless steel vessel (PR), which was long and narrow. Paracetamol solutions in acetone were kept in a glass beaker at controlled temperature (TIC4) and introduced to the nozzle using a high-performance liquid chromatographic pump (P2, FIC2). Intimate contacting of the solution and the antisolvent streams is achieved within the nozzle, where particles are formed. Pressure in the jacketed, temperature-controlled (HE1, TIC2) precipitation vessel is maintained by an electronically heated back-pressure regulator (CV, PIC1). A sintered metal filter is mounted in the exit line, thus preventing any solid material from leaving the pressure vessel. The fluid mixture exiting the vessel is additionally preheated before the downstream BPR (HE2), to avoid solids formation in the valve. The unit is secured by a rupture disk and a safety valve. The experimental setup used for the second set of PCA runs (unit 2) is shown in Figure 2. CO2, flowing in parallel from three dip-tube cylinders, is dried in a silica gel column and compressed to the operating pressure by a pneumatically operated gas booster. After passing a surge tank immersed in a temperature-controlled water bath, where pressure fluctuations are dampened, it enters the precipitation chamber through the con-

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Figure 2. PCA setup at the Unversity of Kansas (unit 2). Details are provided in the text.

from Carba (Basel, Switzerland) and used as received. Analytical-grade acetone (>99.5%) was purchased from Merck (Darmstadt, Germany) and used without further purification. Pharmaceutical-grade paracetamol (>99.0%) was obtained from Merck (Merck-Schuchardt, Hohenbrunn, Germany). PSDs of the paracetamol precipitates were measured using a Sympatec Helos laser light diffraction particle sizer (Sympatec, Clausthal-Zellerfeld, Germany) and an Aerosizer particle sizer (equipped with an Aerodisperser; TSI, Aachen, Germany). Sympatec samples were prepared by suspending particles in 50 mL of White Spirit (terpenalin; Fluka, Buchs SG, Switzerland) and applying ultrasonication for typically 180 s to break the agglomerates in the suspension. In the Aerosizer measurements, the feed rate was set to medium, deagglomeration was high, and pin vibration was on. It must be pointed out that, in the case of the smaller particles produced by PCA, the Aerosizer provided more accurate results in contrast to the case of the larger and more fragile particles obtained with the GAS technique, for which the particle size was determined by scanning electron microscopy (SEM) image analysis. In view of the orders of magnitude disparity in the average size of the particles obtained with the two processes, possible effects of the different measurement techniques on the measured particle sizes are negligible. With reference to unit 2, industrial-grade CO2 was supplied by Airgas Ltd., paracetamol (99.3%) was obtained from Mallinckrodt USP, and acetone was obtained from Fisher Scientific. The PSDs were measured through Aerosizer measurements (API, Amherst, MA), while the particle morphology and structural information were obtained by observations of the SEM photomicrographs. 3. Precipitation of Paracetamol Using the GAS Process

Figure 3. Scheme of the nozzles used in this investigation: (a) coaxial nozzle with a converging-diverging annulus used in unit 2; (b) Schlick 970-S8 nozzle used in unit 1.

verging-diverging annulus of a coaxial nozzle located inside the narrow 2 L precipitator vessel. The solvent (acetone), containing dissolved paracetamol, is supplied at a constant flow rate by a syringe pump (Isco 314), heated by passing through a coil immersed in a water bath, and fed through the inner capillary of the nozzle (0.19 mm) into the temperature-controlled precipitation chamber. The coaxial CO2 stream in the convergingdiverging nozzle rapidly disperses the liquid jet, and precipitation takes places at the exit of the nozzle. A cylindrical glass inlet tapering off into a funnel at the bottom is directing the flow toward the outlet. The particles are collected outside of the reactor on a filter unit, kept at constant temperature by being immersed in the water bath. The CO2-solvent mixture is depressurized over a micrometering valve and the solvent recovered in a cyclone. Finally, Figure 3 shows a sketch of the nozzle types installed in the two PCA units used in this investigation. 2.2. Materials and Methods. With reference to unit 1, technical-grade CO2 (99.9% purity) was purchased

A GAS experiment can be viewed as consisting of three steps. First, the solid material is solubilized in a conventional solvent, e.g., acetone, ethanol, or DMSO, and the solution is loaded into the precipitation vessel. Second, antisolvent addition to the precipitator starts, the pressure increases, and CO2 is transferred from the vapor phase to the solute-rich liquid phase. Thereupon, the solution is expanded, causing its solvent power to decrease and thus triggering solute precipitation. Following precipitation, excess organic solvent is flushed from the reactor and removed from the particles by blowing supercritical CO2 (sc-CO2) at constant pressure. The vessel is then depressurized and the final product recovered. During the precipitation phase, the CO2 is transferred from the vapor phase to the liquid phase and hence the volume expansion rate depends on the rate of the pressure increase, i.e., on the rate of CO2 addition to the precipitator. On the basis of previously reported experimental investigations, three different patterns of behavior were observed in terms of the effect of the specific CO2 addition rate, QA, which is defined as the ratio between the CO2 flow rate and the initial amount of solution.11-14 In the case of a proprietary organic compound, the average particle size decreased with increasing QA and PSD was unimodal at low and high addition rates and bimodal at intermediate values of QA.11,12 On the contrary, in the case of lysozyme, the average particle size remained unaffected by variations of the CO2 addition rate. When the GAS precipitation

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Figure 4. Effect of the specific CO2 addition rate on the average size of paracetamol particles obtained in the GAS experiments: T ) 25 °C, relative saturation S0 ) 0.8, precipitator volume VGAS ) 400 mL, stirring rate n ) 500 rpm.

Figure 5. Effect of the specific CO2 addition rate on the supersaturation ratio and average particle size in the GAS process calculated using the model described in ref 15.

Table 1. Operating Conditions of the Paracetamol GAS Experiments: T ) 25 °C, Relative Saturation S0 ) 0.8, Precipitator Volume VGAS ) 400 mL, and Stirring Rate n ) 500 rpm in All Experiments Listed run

M0 [g]

MCO2 [g/min]

QA [min-1]

xjvol [µm]

P01 P02 P03 P04 P06 P07 P08 P10 P11 P13

75 50 50 50 50 50 50 15 15 15

5 5 10 10 30 30 50 30 30 50

0.067 0.1 0.2 0.2 0.6 0.6 1 2 2 3.33

230 250 150 200 190 190 150 90 130 87

of paracetamol from acetone was investigated, a major effect of QA on the final product quality was observed as well.13 In the case of both lysozyme and paracetamol, the PSD was always unimodal. Table 1 lists a series of paracetamol precipitation experiments carried out at 25 °C and reports the following operating parameters together with the crystal characteristics: initial solvent amount M0, CO2 addition rate MCO2, specific addition rate QA, and final average particle size xjvol. Figure 4 illustrates the effect of the CO2 addition rate on the average particle size of the paracetamol crystals. When QA is increased between 0.067 and 3.33 min-1, the average particle size decreased from about 250 µm to about 87 µm, i.e., an approximately 3-fold decrease. As discussed elsewhere, the results indicate a satisfactory reproducibility.13 The morphology of the paracetamol particles was found to be dependent on the level of supersaturation attained during a specific experiment. In the series of runs at 25 °C listed in Table 1, increasing supersaturation (i.e., QA) leads to a transition from a more equant shape to a prismatic morphology.13 It is worth mentioning that supersaturation is defined as15

S)

fP,L(x,p,T) fP,P(p,T)

(1)

where fP,L indicates the fugacity of the solute in the liquid phase (depending also on the liquid composition x), whereas the denominator is the fugacity of the pure solid.

Figure 6. Location of the PCA experiments with paracetamol in the p-T diagram of the binary system CO2-acetone.

Simulations using the GAS mathematical model mentioned in the Introduction shed light on the mechanism by which the specific CO2 addition rate controls the final average particle size. Let us consider the model system phenanthrene-toluene-CO2 adopted in our theoretical study and the case where primary nucleation prevails, while secondary nucleation is assumed to be negligible.15 As illustrated in Figure 5, increasing QA increases the supersaturation build-up rate in the batch system, resulting in higher supersaturation levels and progressively greater nucleation rates (open boxes in Figure 5). Because nucleation and growth consume the supersaturation, a larger number of nuclei (at higher nucleation rates) will grow to a smaller final size and vice versa (dots in Figure 5). In short, in the GAS process, QA controls the supersaturation ratio and thereby the nucleation rate, which, in turn, dictates the final particle size. 4. Results 4.1. Precipitation of Paracetamol Using the PCA Process. The PCA precipitation of paracetamol from acetone solutions was studied in the 83-120 bar pressure range and in the 33 and 62 °C temperature range in the two units described above. Experimental conditions and particle properties are reported in Table 2 and

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Figure 7. Paracetamol precipitated with the PCA technique in (a) run S04 at p ) 95 bar and T ) 38 °C and (b) run S05 at p ) 120 bar and T ) 50 °C. Table 2. Operating Conditions of the Paracetamol PCA Experiments and Characteristics of the Microparticles Precipitated run

unit

T [°C]

p [bar]

region

MCO2 [g/min]

V˙ sol [mL/min]

S0

xjnum [µm]

morphology

S01 S02 S03 S04 S05 S06 S07 S08 S09 S10 S11 S12 S13 S14

2 2 2 2 1 2 2 2 1 1 2 2 1 2

33 33 33 38 50 38 38 38 38 47 47 47 47 62

83 83 83 95 120 83 83 83 83 95 83 83 83 95

A A A A A A A A A A B B B B

138 138 138

4 4 4

0.5 0.5 0.5

70 138 138 138 70 70 138 138 70 70

1 4 4 4 1 1 4 4 1 1

0.8 0.4 0.4 0.4 0.8 0.8 0.3 0.3 0.8 0.8

2 2 2 2.2 2 2 1.5 1.7 1.3 1.4 2.5 2.5 2.5 2.0

a a a a a b b b b b b b b b

illustrated in Figure 6. The following information is reported for each run in Table 2: the operating temperature and pressure, which are represented in the p-T diagram (Figure 6) relative to the critical locus; the CO2 flow rate, MCO2; the solution flow rate, V˙ sol, and its concentration in terms of relative saturation, S0, which is defined as the ratio between the actual solute concentration and the saturation concentration at a specific experimental temperature; the average numberweighted particle size xjnum; the observed particle morphology (a or b). X-ray powder diffraction measurements showed that the stable monoclinic form I of paracetamol was obtained in all experiments. The SEM photomicrographs show two different particle morphologies: moderately agglomerated crystals with distinguishable crystal faces, on the one hand (indicated as morphology a and shown in Figure 7), and highly agglomerated spheroidal particles with undistinguishable crystal faces, on the other hand (indicated as morphology b and shown in Figure 8). These observations are consistent with those of Bristow et al.16 The PSDs measured were in general rather broad either because of agglomeration as observed in the SEM photomicrographs or possibly because of flow pulsations at the nozzle, resulting in suboptimal atomization of the droplets. PSDs were measured using the Aerosizer and reported in terms of the number-weighted particle size, xjnum. The volume-weighted particle sizes obtained using Sympatec HELOS measurements for some test runs attained values 5-10-fold higher than xjnum, as expected.

The particle size results are conveniently analyzed in terms of the location of the corresponding operating conditions relative to the acetone-CO2 critical locus in the p-T diagram of Figure 6. Below the critical locus (region B in Figure 6), an acetone-rich phase and a CO2rich phase coexist, whereas a single phase exists above the line (region A in Figure 6). While the effects of the solution and antisolvent flow rates have not been thoroughly investigated, we have carefully analyzed the effect of the initial solution saturation, S0, in a series of 20 runs that are not reported here in detail for the sake of brevity. These runs were carried out under the same conditions as runs S06 and S07 in Table 2 but with variance of S0 between 0.1 and 0.65. Similar particle size results were observed in all of these experiments, with rather broad PSDs and average particle sizes similar to those of runs S06 and S07. Some scattering is observed in the case of repeated runs, with the average particle size varying by as much as a factor 2. However, no clear trend is observed when S0 is increased. On the basis of these results, we assume that for this system S0 has no major effect on the particle size at the conditions investigated. From Table 2, it can be readily observed that the average particle size is essentially constant around 2 µm in all of the experiments and is 2 orders of magnitude smaller than that obtained in GAS experiments. However, operating conditions affect the morphology of the precipitate, as seen in Figure 7 with reference to runs S04 and S05 and in Figure 8 with reference to runs

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Figure 8. Paracetamol precipitated with the PCA technique in (a) run S09 at p ) 83 bar and T ) 38 °C and (b) run S10 at p ) 83 bar and T ) 47 °C.

S09 and S10. It must be noted that the average particle size measured in the case of the morphology b refers to the size of the agglomerates, whereas primary particles have submicron size. Interestingly, as shown in Figure 6, the seven different sets of operating p and T in the PCA experiments cluster distinctly based on the observed particle morphology. As highlighted in Figure 6, operating points well above the critical locus lead to morphology a, whereas those close to and below the critical locus lead to morphology b. It is worth noting that these observations apply to experiments carried out in two different experimental setups. Two mechanisms may be responsible for the formation of agglomerates of spherical nanoparticles. Agglomeration may be favored by the confined volume of the solution droplet, which first swells and then shrinks upon mass exchange with the dense gas.17 On the other hand, the formation of spherical crystals can be due to surface roughening that takes place above the roughening temperature, Tr.16 Our data seem to confirm that Tr is a function of pressure in our system, whose value is a few degrees smaller than the critical temperature at the specified pressure. 5. Discussion The GAS and PCA processes produce particles of significantly different average size, namely, between 90 and 250 µm and about 2 µm, respectively. In the following discussion, we explore the reasons for this difference by systematically analyzing the similarities and differences between the two processes. In both cases, the nucleation of the new solid phase is triggered by the change in the composition of the solution upon contact with the dense gas antisolvent, i.e., sc-CO2. CO2 diffuses into the solution (bulk liquid phase in GAS and the atomized droplets in PCA), while the solvent diffuses out of the solution, thus increasing its supersaturation. In the case of droplets contacted with sc-CO2, Werling and Debenedetti have shown theoretically that, in the two-phase region (region B in Figure 6), a solvent droplet swells when sc-CO2 initially diffuses into it and then shrinks and disappears when the solvent leaves the droplet to diffuse into the dense gas.17 In the region of full miscibility (region A in Figure 6), there is no physical interface separating the droplet from the bulk. Nevertheless, it is possible to define a droplet region by considering the steep concentration

gradient between the solution-rich and CO2-rich domains and defining a virtual interface at a cutoff solvent concentration.18 As in the previous case, the droplet region swells and then shrinks as a result of mass transfer. However, in the region of full miscibility, mass transfer may be controlled by mixing phenomena (rather than by molecular diffusion) influenced by the turbulence generated at the nozzle in a way similar to that of mixing effects in parallel chemical reactions.19-21 The mass-transfer mechanism has also been studied through experiments and modeling in the case of the GAS process.22 In this case, our modeling work indicates that the rate of CO2 transfer from the gas phase to the solution is on the order of the CO2 addition rate. As discussed in the last paragraph of section 3, the average particle size can be tuned in the GAS process by changing the antisolvent addition rate. The foregoing phenomenological considerations motivated us to evaluate the mass-transfer properties in the GAS and PCA processes in terms of the characteristic mass-transfer times. For the GAS process, such a characteristic time is defined as the ratio of the initial amount of solvent and the average CO2 mass-transfer rate, which during expansion equals the CO2 addition rate:22

τGAS mt ) M0/MCO2

(2)

In the case of the paracetamol experiments, τGAS mt varies between 20 s and 15 min, corresponding to a particle size increase from 90 to 250 µm, as illustrated in Figure 9. Let us consider the PCA process and the case where the operating conditions are located inside the twophase region. The simulations of Werling and Debenedetti describe the temporal swelling of a 50 µm spherical toluene droplet in sc-CO2 at T ) 318 K and at different pressure levels.17 In particular, the values of the maximum radius, Rmax, reached during droplet swelling and just before shrinking and of the corresponding time, tmax, are reported in Table 3 and plotted in Figure 10. The volume change corresponding to the change in the radius between the initial value and Rmax is primarily due to transfer of CO2 from the high-pressure atmosphere to the droplet. The corresponding mass-transfer rate is equal to the ratio of the volume change and tmax, the time duration of swelling. Similar to the GAS case,

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Figure 9. Average particle size versus characteristic masstransfer time for the GAS precipitation experiments with paracetamol listed in Table 1. Table 3. Maximum Radius of a Toluene Droplet Surrounded by CO2 and the Time Necessary To Reach It as a Function of Pressure at 318 Ka p [bar]

Rmax [µm]

tmax [s]

PCA [s] τmt

75 82.5 87.25 87.39

90 120 170 158

0.15 0.25 0.38 0.4

0.03 0.02 0.01 0.015

a Data are obtained from the calculations of Werling and Debenedetti.

Figure 10. Maximum radius of a toluene droplet surrounded by CO2 and the time necessary to reach the maximum value as a function of pressure at 318 K. Data are obtained from the calculations of Werling and Debenedetti.17

an estimate of the characteristic mass-transfer time may be obtained from the initial volume and this estimated flow rate as follows:

τPCA mt ) tmaxV0/(Vmax - V0)

(3)

values The data reported in Table 3 indicate τPCA mt between 0.01 and 0.03 s. Assuming 2-fold uncertainty on the initial droplet size and given that the characteristic diffusion time scales with the square of the characteristic length, the corresponding uncertainty in is 4-fold, i.e., a maximum value of about 0.1 s. τPCA mt This value is on the same order of magnitude as those reported for operating conditions in the region of full miscibility.18 In presence of turbulent mixing, the mass-

Figure 11. Average particle size as a function of the characteristic mass-transfer time calculated using the GAS model presented in ref 15.

transfer rates will be enhanced, resulting in even 19 smaller estimates of τPCA mt . The conclusion therefore is that the largest estimate of the characteristic mass transfer in the PCA process is at least 2 orders of magnitude smaller than the smallest estimate of the characteristic mass-transfer time in the GAS process. We have already demonstrated through Figures 5 and 9 that, in the GAS process, τGAS mt controls the supersaturation level at which nucleation occurs, which, in turn, dictates the final particle size. On the basis of these observations, we speculate that much higher supersaturation levels are accessible in the PCA process than in the GAS process, resulting in much higher nucleation rates and finally in much smaller particles, as observed in our experimental investigation. In other words, the disparity in the particle size obtained via the two processes would be mainly due to significant differences in the mass-transfer rates in the two cases, with the underlying mechanisms governing precipitation being essentially the same in the two processes. To verify this speculation, one would have to run a GAS experiment at a CO2 addition rate much higher than what is feasible in practice, i.e., at a flow rate where mixing in the GAS precipitator would most likely still be rate-controlling. A viable alternative is to perform simulations using the GAS model to interpret the results illustrated in Figure 5.15 With the model, the characteristic mass-transfer times of the PCA process can be simulated by selecting corresponding values for the CO2 addition rate and for the initial solution volume and by assuming perfect mixing in the precipitator. For the model system phenanthrenetoluene-CO2, Figure 11 shows the results of simulations performed over a broad range of values of the characteristic mass-transfer time, i.e., including those typical of both PCA (left-hand side of Figure 11) and GAS (right-hand side of Figure 11). The predicted trend in Figure 11 confirms our hypothesis. At the conditions prevailing in the PCA process, the model predicts particle sizes that are nearly 2 orders of magnitude smaller than those in the GAS process. This difference correlates with the different characteristic mass-transfer times in the two cases, which is a generic property of the two processes.

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6. Conclusions Compressed CO2 has been used to precipitate paracetamol from acetone by the PCA technique. The experimental investigations addressed the study of the operating parameters pressure, temperature, and concentration in two different experimental units equipped with different injection devices. In both units, similar operating conditions produced particles with remarkably similar characteristics (size and morphology). The particle characteristics obtained using the PCA technique were compared to those obtained for the same system by the GAS process. The PCA process yielded particles that are 2 orders of magnitude smaller than those obtained in the GAS process. In both processes, the mass-transfer rate of the antisolvent into the solution phase controls the supersaturation level, a key determinant of the nucleation rate and the eventual particle size. Hence, we investigated how the characteristic mass-transfer time associated with this mechanistic step correlates with the particle sizes obtained in the two processes. Characteristic mass-transfer times, estimated for the GAS and PCA processes, showed a 2 orders of magnitude difference, which mirrors disparity in the average particle size obtained in the two processes. This result shows that, for at least the paracetamol system, the GAS and PCA processes may be described in a continuum of characteristic mass-transfer times, with the underlying particle formation mechanism being identical. If confirmed by a similar investigation carried out on other systems, this type of analysis can contribute to a better understanding of these two important techniques and to the possibility of exploiting them more effectively to produce particles with the desired properties. Acknowledgment The support provided to M.H. as a part of the University of Kansas-ETH Zurich student exchange program is gratefully acknowledged. Literature Cited (1) Subramaniam, B.; Rajewski, R. A.; Snavely, K. Pharmaceutical processing with supercritical carbon dioxide. J. Pharm. Sci. 1997, 86, 885-890. (2) Jung, J.; Perrut, M. Particle design using supercritical fluids: Literature and patent survey. J. Supercrit. Fluids 2001, 20, 179-219. (3) Rogers, T. L.; Johnston, K. P.; Williams, R. O., III. Solutionbased particle formation of pharmaceutical powders by supercritical or compressed fluid CO2 and cryogenic spray-freezing technologies. Drug Dev. Ind. Pharm. 2001, 27, 1003-1015. (4) Kompella, U. B.; Koushik, K. Preparation of drug delivery systems using supercritical fluid technology. Crit. Rev. Ther. Drug Carrier Syst. 2001, 18, 173-199. (5) Thiering, R.; Dehghani, F.; Foster, N. R. Current issues relating to anti-solvent micronisation techniques and their extension to industrial scales. J. Supercrit. Fluids 2001, 21, 159-177.

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Received for review June 10, 2004 Revised manuscript received September 17, 2004 Accepted December 6, 2004 IE049495H