Gas Antisolvent Recrystallization of Paracetamol from Acetone Using

CRYSTAL GROWTH & DESIGN 2004 VOL. 4, NO. 5 881-889

Articles Gas Antisolvent Recrystallization of Paracetamol from Acetone Using Compressed Carbon Dioxide as Antisolvent Francesco Fusaro and Marco Mazzotti* ETH Swiss Federal Institute of Technology Zurich, Institute of Process Engineering, Sonneggstrasse 3, CH-8092 Zurich, Switzerland

Gerhard Muhrer Novartis Pharma AG, Chemical & Analytical Development, CH-4002 Basel, Switzerland Received September 17, 2003;

Revised Manuscript Received December 11, 2003

ABSTRACT: Paracetamol was precipitated from solution in acetone using compressed carbon dioxide (CO2) as an antisolvent in a batch gas antisolvent (GAS) recrystallization process. In this study, the effect of specific carbon dioxide addition rate (0.067-6.0 min-1), temperature (5-40 °C), relative solute concentration in acetone (0.5-0.9), and stirring rate (150-1000 rpm) on product quality was investigated. The average particle size of the monoclinic paracetamol crystals was successfully controlled between 50 and 250 µm by changing the specific CO2 addition rate accordingly in a range spanning about 2 orders of magnitude. It was demonstrated that, in agreement with previous studies and theoretical investigations, the mean particle size decreases when the antisolvent addition rate is increased. Increasing the operating temperature led to an increase of the mean crystal size, while altering the concentration of the starting solution showed virtually no effect. As it would be expected, high stirrer speeds favored mechanical comminution, thus increasing the fines fraction in the recovered product. The results obtained in the experiments carried out in a 1-L precipitator are qualitatively and quantitatively in good agreement with those obtained in a 400-mL precipitator, thus once more underlining the robustness of GAS recrystallization. Residual solvent content in the dry product and yield were always within acceptable limits in both experimental facilities. The crystal habit obtained and the effect on it of the operating conditions are consistent with previous literature results. 1. Introduction There is an increasing interest in the specialty chemical and pharmaceutical industries to develop technologies that can produce micron or submicron size solid particles with controlled particle size distribution (PSD). GAS recrystallization is a promising process that in principle allows mean particle size, PSD, morphology, and purity to be controlled under mild and inert operating conditions. In GAS recrystallization, the solute is first dissolved in an organic solvent, and then a gaseous antisolvent is gradually added to the solution. In most practical applications, CO2 is used as antisolvent due to its mild critical temperature (31.1 °C) and pressure (73.8 bar), its nontoxicity, and low price. During antisolvent addition, the solution is volumetrically expanded as CO2 is solubilized in the liquid phase, and pressure increases from ambient to the dense fluid * To whom correspondence should be addressed. Phone: +41-16322456. Fax: +41-1-6321141. E-mail: [email protected].

region. The solubilization of CO2 in the liquid phase consequently lowers its solvent power, eventually triggering precipitation of the solute. GAS recrystallization ranks among several high pressure gas assisted particle formation processes that have been proposed and recently reviewed.1-5 Paracetamol (acetaminophen, 4-hydroxyacetanilide: C8H9NO2) is a classical over-the-counter analgesic and anti-pyretic drug commonly administered as tablets or in hot, aqueous solution, and has frequently been used as a model drug compound in the scientific literature. For example, a considerable amount of work is reported covering different aspects of paracetamol crystallization, e.g., its solubility in organic solvents,6 the effect of process parameters on crystal growth and crystal properties,7 the dissolution behavior of paracetamol particles,8 or the occurrence of multiple paracetamol polymorphs.9 The GAS recrystallization of paracetamol from an ethanol solution has been studied by Wubbolts.10 In this contribution, starting solutions were pressurized

10.1021/cg034172u CCC: $27.50 © 2004 American Chemical Society Published on Web 01/22/2004

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with helium prior to CO2 addition. Some indications of how antisolvent addition rate, final solvent-to-antisolvent ratio, initial solution concentration, and stirrer speed affect product quality are also provided. The same group investigated the recrystallization of paracetamol from an ethanol solution using a precipitation with compressed antisolvent (PCA) spray process approach. This technique is actually rather similar to the GAS process that we are considering. In fact, in PCA the organic solution is sprayed into compressed carbon dioxide, thus creating very high supersaturations and generally yielding very small particles. In this study, Wubbolts and co-workers observed that the mixture critical point had a crucial effect on PCA operation, i.e., large particles about 200 µm in size were obtained at subcritical conditions relative to the mixture critical locus, whereas fine particles around 1-5 µm were harvested when both pressure and temperature were above their critical values for the CO2-ethanol binary system.10 Bristow and co-workers observed a transition from spherical to prismatic shape in particle morphology when operating conditions were subcritical and supercritical with respect to the mixture critical locus in the same system, respectively.11 Shekunov and co-workers also used a PCA process for the precipitation of paracetamol from ethanol, and report the crystal habit of paracetamol particles to depend strongly on the bulk CO2 density. Moreover, the solubility of paracetamol in mixtures of CO2 and ethanol was found to increase substantially at a pressure above 250 bar, thus negatively affecting the primary nucleation rate, and eventually entailing larger particles.12 The same authors later reported an investigation of the spray fluid dynamics in PCA precipitation.13 Our group has recently investigated the effect of operating parameters on product quality in the GAS recrystallization of a nondisclosed pharmaceutical intermediate14,15 and of lysozyme.16 Whereas the CO2 addition rate was successfully used to tailor the mean particle size of the drug compound in a range spanning almost 2 orders of magnitude, i.e., between about 100 nm to about 10 µm, the same parameter had virtually no effect on product quality in the case of the model protein. This conflicting behavior can be explained using a detailed mathematical model of GAS recrystallization, suggesting the final particle size to be primarily controlled by the relative intensity of primary and secondary nucleation. In fact, it was shown that the rate of antisolvent addition can be effectively used to control the average particle size in systems where primary nucleation is dominant with respect to secondary nucleation, whereas process parameters hardly have an effect on product quality when the opposite occurs.17 In this work, we report on the GAS recrystallization of paracetamol from an acetone solution. In particular, we systematically investigate the effect of operating parameters, namely, specific CO2 addition rate, temperature, initial solution concentration, and stirring rate, on product quality. The experimental work is carried out in two different precipitators with different overall volumes to address the key issue of process robustness and scale-up feasibility. Moreover, we assess to what extent the results obtained for this system can

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be rationalized in the light of the recently proposed detailed model of the GAS recrystallization process.17 2. Experimental Section 2.1 Experimental Setup. Two different experimental facilities were used in this work, with precipitator total volumes of 400 mL (unit 1, at ETH Zurich) and 1000 mL (unit 2, at Novartis Pharma), respectively. The jacketed, temperature controlled 400-mL precipitator in unit 1 allowed for the full visual observation of the liquid-phase volume expansion and precipitation processes upon carbon dioxide addition through a lengthwise Pyrex window (H ≈ 120 mm). Carbon dioxide was delivered to the precipitation vessel at constant mass flow rate and at operating temperature, and feeding was accomplished through the impeller shaft, i.e., carbon dioxide was bubbled into the liquid phase. This mode of GAS recrystallization operation has recently been demonstrated to feature favorable vapor-liquid mass transfer characteristics.18 Particles were collected on a sinter metal filter mounted at the bottom of the precipitation vessel. Heating and controlled depressurization was applied to the fluid mixture leaving the vessel after each experiment to avoid formation of dry ice in the downstream valves and lines. All process data were acquired electronically using LABWIEV and recorded on a personal computer. A detailed description of unit 1 may be found elsewhere.16,19 Unit 2 is rather similar to unit 1, the main difference being that carbon dioxide enters the jacketed, temperature-controlled precipitator from the bottom of the vessel rather than through the impeller. Unit 2 has also been described in more detail elsewhere.15,19 2.2 Materials and Methods. Technical grade carbon dioxide (99.9% purity) was purchased from PanGas (Schlieren, Switzerland) and used without further purification. Analytical grade acetone (99.7%) was purchased from Fluka (Buchs SG, Switzerland) and used as supplied. Pharmaceutical grade paracetamol (g99%) was obtained from Merck (Merck-Schuchardt, Hohenbrunn, Germany). Paracetamol has a molecular weight of 151.17 g/mol and appears as a white, crystalline powder at standard conditions. It melts between 168 and 172 °C, and its solubility in acetone is about 100 g/kg of solvent at 25 °C. A detailed investigation of its solubility in a wide variety of solvents is provided elsewhere.6 Two polymorphic forms of paracetamol can be produced by crystallization from solution, i.e., the monoclinic (I), and orthorombic (II) forms, respectively, being polymorph I the thermodynamically stable form. A third, unstable polymorph was recrystallized and identified recently.20 Precipitate morphologies in this study were compared to the starting material using X-ray powder diffraction. The properties of the paracetamol particle populations were determined by scanning electron microscopy (SEM) for shape and size, X-ray powder diffraction for morphology, and HPLC for purity. Particle size distributions were measured using Sympatec HELOS (Clausthal-Zellerfeld, Germany) and AEROSIZER (equipped with an AERODISPERSER; TSI, Aachen, Germany) analytical instruments. The samples for SEM analysis were prepared by Platinum sputtering (7 nm), and photomicrographs were recorded on a Hitachi S-900 cold cathode field emission scanning electron microscope. Crystal habit, extent of agglomeration, irregularities and fractures in the crystals, and presence of breakage fragments were determined qualitatively based on the SEM photomicrographs. Average particle size and particle size distribution were obtained through image analysis, and through standard offline analytical tools. In the first case, this was achieved through quantitative analysis of the SEM photomicrographs, i.e., by identifying the primary particles manually, and by letting a software tool compute the relevant statistics; at least 250 particles per sample were considered to properly catch the statistics. This time-consuming procedure allows to distinguish cleraly between primary particles, agglomerates, and fragments, thus yielding a rather precise characterization of the particle population. Image analysis results were than com-

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Table 1. Operating Conditions of the GAS Experiments and Characteristics of the Microparticles Precipitateda run

V [ml]

M0 [g]

T [°C]

S0 [-]

QA [min-1]

n [rpm]

xjvol [µm]

σ [µm]

c.v. [-]

P01 P02 P03 P04 P05 P06 P07 P08 P09 P10 P11 P12 P13 P14 P15 P16 P17 P18 P19 P20 P21 P22 P23 P24 P25

400 400 400 400 1000 400 400 400 1000 400 400 1000 400 1000 1000 400 1000 400 400 400 400 400 400 400 400

50 50 50 50 50 50 50 50 50 15 15 50 15 50 50 50 50 50 15 50 15 50 50 50 50

25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 5 5 5 5 40 40 25 25 25 25

0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.5 0.9 0.8 0.8

0.067 0.1 0.2 0.2 0.2 0.6 0.6 1 1 2 2 2 3.33 3.33 6 0.2 0.2 0.6 2 0.2 2 0.6 0.6 0.6 0.6

500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 150 1000

230 250 150 200 160 190 190 150 58 90 130 43 87 69 49 120 71 160 140 270 170 190 170 250 140

71 70 52 73 65 56 66 47 19 26 34 16 13 26 17 41 24 55 50 98 41 62 52 74 44

0.31 0.29 0.35 0.36 0.41 0.29 0.35 0.31 0.33 0.28 0.27 0.37 0.15 0.38 0.35 0.35 0.34 0.34 0.36 0.36 0.24 0.32 0.31 0.30 0.31

figure 2

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7 7 9 9 11 11

morphology b, (a) b, (a) b, (a) b, (a) b, (a) a, (b) b, (a) b, (a) b, (a) a, (b), (c) b, (a) b, (a) b, (a), (c) b, (a) b, (a) b b b, (a) c b b b, (a) b, (a) a, (b) b

a With respect to the crystal morphology, a, b, and c indicate a columnar, a more equant, and a flat tabular habit, respectively. The less frequent types are reported between brackets.

pared to AEROSIZER and Sympatec HELOS measurements. Shear force and feed rate were set to medium, deagglomeration was high, and pin vibration was on, in the AEROSIZER measurement. Particle samples were suspended in about 50 mL of toluene and sonicated for typically 40 s prior to analysis on the Sympatec HELOS laser light diffraction instrument. Reproducibility of the individual measurements was duly checked, and good agreement was found between AEROSIZER and Sympatec HELOS results. It is worth noting that average particle sizes were slightly larger compared to image analysis for both methods used. The residual solvent content in the precipitates was measured on a Waters (Milford, MA) HPLC chromatograph. A NUCLEOSIL 100-5 C18 HD column was used, either pure water or water-ethanol mixtures were used as eluents at a flow rate of typically 0.8 mL/min, and the UV detector was operated at a wavelength of 254 nm. 2.3 Experimental Procedure. Batches of paracetamol in acetone were prepared (between 15 and 55.5 g of solution) at concentrations varying between 50 and 90% of the equilibrium solubility at the operating temperature, and loaded into the precipitators of either unit 1 or unit 2. Either precipitation vessel was then closed and the liquid solution stirred at a constant rate of typically about 500 rpm for 30 min. When the operating temperature and the desired flow rate were sufficiently stable, CO2 was fed to the precipitator with the outlet valve closed. Feed flow rates corresponding to specific antisolvent addition rates between 0.067 and 3.3 min-1 in unit 1 and between 0.2 and 6 min-1 in unit 2 were then kept constant until the precipitation vessels were completely filled with liquid, and the desired final pressure was reached. Depending on the actual CO2 addition rate, feeding times were between 60 and 6 min in unit 1 and between 90 and 12 min in unit 2. The final liquid expansion ratios ∆V/V0 reached values between about 800 and 2600% in unit 1, and between 1800 and 6200% in unit 2, depending on the initial solution volume. After full expansion, the CO2 supply was shut off, and the system was allowed to reach equilibrium for typically 1 h, while stirring was continued. Then the outlet valve was opened, and flushing with pure CO2 at the final pressure was initiated. In unit 1, flushing to remove the organic solvent from the product was continued for typically 2 h at a constant CO2 flow rate of about 30 g/min. A similar procedure was adopted for unit 2, where flushing at constant pressure was continued for a minimum of 5 h at a flow rate of typically about 20 g/min.

Figure 1. Damages of the crystal surface and fines due to mechanical comminution observed in the precipitate of run P06. After depressurization, the precipitators were opened, and the dry solid content was harvested for off-line analysis.

3. Results and Discussion A total of 25 experimental runs were carried out in this study, 19 of which in unit 1, and 6 in unit 2, as reported in Table 1. X-ray powder diffraction analysis of the starting material and of the GAS precipitates demonstrated that the stable monoclinic form (form I) of paracetamol was obtained upon gas antisolvent recrystallization from acetone using CO2 as antisolvent at all operating conditions investigated. Moreover,

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Figure 2. SEM photomicrographs of the microparticles precipitated in run P02 and corresponding volume PSD. T ) 25 °C, QA ) 0.1 min-1, S0 ) 0.8, n ) 500 rpm.

Figure 3. SEM photomicrograph of the microparticles precipitated in run P06 and corresponding volume PSD. T ) 25 °C, QA ) 0.6 min-1, S0 ) 0.8, n ) 500 rpm.

particle size distributions of the particle populations harvested from both precipitation vessels were typically rather broad, and exhibited a low to moderate degree of agglomeration. The broadness of the PSDs is mainly due to the presence of fines formed by mechanical comminution. This is mainly caused by particle-stirrer, but also particle-particle, and particle-wall collisions, and is clearly manifested in the SEM photomicrographs by discernible irregularities and fractures in the crystal surfaces, as well as by the presence of a significant amount of fine, irregular fragments, as shown in Figure 1. The residual acetone content in the paracetamol particles was measured using HPLC, and analyzed as a function of flushing time, total amount of makeup carbon dioxide used for the flushing step, and operating temperature during the flushing step. Residual acetone contents were typically well below 0.1 weight percent, provided that the total amount of makeup carbon dioxide was sufficient (i.e., g3 kg for unit 1, and g5 kg

for unit 2), and that the flushing temperature was high enough. As expected, in general high temperatures favor the removal of residual solvent from the precipitates. For example, with reference to Table 1, while the total amount of CO2 flushed was higher in run P18 (4.7 kg) at 5 °C than in run P06 (3 kg) at 25 °C the residual solvent content was only 331 ppm in the latter but 1600 ppm in the former. It is clear that virtually contaminantfree particles may be obtained upon GAS recrystallization, when flushing after full expansion is intense enough. However, economical considerations may require this point to be assessed in more detail to find an optimal tradeoff between antisolvent requirement and energy consumption on one hand, and product purity on the other hand for any practical application of this technology. For all 25 experiments, Table 1 reports the following information: the size of the precipitator; the initial amount of solvent M0; and its concentration in terms of supersaturation S0, which is defined as the ratio of the



Figure 4. SEM photomicrograph of the microparticles precipitated in run P10 and corresponding PSD. T ) 25 °C, QA ) 2 min-1, S0 ) 0.8, n ) 500 rpm.

Figure 5. Effect of the specific carbon dioxide addition rate on the average particle size at 25 °C, initial saturation S0 ) 0.8 and stirring rate n ) 500 rpm. Symbols: (b) experiments carried out in experimental setup 1 (400-mL precipitator); (3) experiments carried out in experimental setup 2 (1000-mL precipitator).

Figure 6. Effect of temperature on the average particle size at initial saturation S0 ) 0.8 and stirring rate n ) 500 rpm. Symbols: (]) experiments carried out at a specific antisolvent addition rate of 0.2 min-1; (2) experiments carried out at a specific antisolvent addition rate of 2 min-1.

actual solute concentration in the starting solution to the corresponding solubility at the operating temperature, which is also reported; the specific carbon dioxide addition rate QA, defined as the antisolvent mass flow rate per unit amount of initial solution; and the stirring frequency n. The produced particles are characterized in terms of the average size of the volume distribution xjvol, the standard deviation σ, and the coefficient of variation c.v. It is worth noting that the c.v. is rather homogeneous among the experiments, with values between 0.15 and 0.40 that do not exhibit any significant trend. Finally, for each run, the more frequent crystal morphology observed in the corresponding SEM photomicrographs is reported, together with the less frequent one between brackets. The terminology used is in accordance with previous studies on the morphology of paracetamol crystals grown from aqueous solutions.7,21,22

In Table 1, the letters a, b, and c indicate a columnar, a more equant, and a flat tabular habit, respectively. The experiments are labeled P01-P25, and grouped in terms of effect investigated in the series of runs in both experimental facilities, i.e., experiments P01-P15 were carried out at increasing values of the specific carbon dioxide addition rates at otherwise constant operating parameters, whereas the effects of temperature, initial solution concentration, and stirrer speed were studied in runs P16-P21, P22-P23, and P24-P25, respectively. 3.1 Effect of the Specific Carbon Dioxide Addition Rate. First, let us consider experimental runs P01-P15 in Table 1. These refer to experiments carried out in either unit 1 or unit 2 at a temperature of 25 °C, an initial solution concentration corresponding to 80% of the solubility value, and at a stirrer speed of 500 rpm, allowing for sufficiently rapid CO2 transfer from the

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Figure 7. Effect of temperature at QA ) 2 min-1, S0 ) 0.8 and n ) 500 rpm. SEM photomicrograph of the microparticles precipitated in (a) run P19 at T ) 5 °C; (b) run P21 at T ) 40 °C.

vapor to the liquid phase.18 These runs are listed in Table 1 in the order of increasing specific antisolvent addition rate QA, which varies over almost 2 orders of magnitude, i.e., between 0.067 and 6 min-1. It is worth pointing out that experimental runs carried out in different setups featuring different precipitator geometries and volumes, as well as different antisolvent delivery systems, are most effectively compared on the basis of the specific antisolvent addition rate, QA, as previously demonstrated.14,15 The photomicrographs and PSDs of the particles obtained in runs P02, P06, and P10 are shown in Figures 2, 3, and 4, respectively. The decrease in average size in going from the low to the high addition rate can be clearly observed visually, as well as by analyzing the rather broad PSDs. Despite PSDs exhibit a mild bimodality, we do not attribute this to the occurrence of two separate nucleation events during precipitation, as we did in a previous investigations on a different organic compound.14,15 In fact, contrary to the present case the bimodality was visually very evident (see for instance Figure 5 in our previous paper14), and the particle sizes corresponding to the two maxima in PSD were much more separated, i.e., by up to 1 order of magnitude (see runs E25D and E25E in Table 1 in our previous paper14). To highlight the observed trend, the average particle size, xjvol, obtained in runs P01 through P15 is plotted vs the specific antisolvent addition rate, QA, in Figure 5. In general, experimental points lie on a curve with negative slope. This is true for experiments run in both setups, i.e., in the 400-mL reactor (circles) and in the 1-L reactor (triangles), even though the dependence of xjvol on QA in the two cases might be slightly different. The reproducibility of the results in the 400-mL reactor is excellent in one case, namely, runs P06 and P07, good in general, and less satisfactory in at least one case, i.e., runs P10 and P11. In general, however, the behavior of the corresponding experimental points (circles) in Figure 5 is rather regular, thus pointing at a satisfactory accuracy of the results. Despite the different CO2 supply modes adopted in the two units that can influence mass transfer rates, the results obtained in the two reactors under the same conditions are consistent with each

Figure 8. Effect of the initial saturation on the average particle size at 25 °C, QA ) 0.6 min-1 and n ) 500 rpm.

other, with a rather significant difference in average size only at QA ) 1 min-1 (P08 and P09). It is worth noting with reference to Figure 5 that the type of dependence of the mean particle size on the antisolvent addition rate is one of the three patterns of behavior that has been identified through the use of model simulations in a recent work.17 The other two have already been observed experimentally, and correspond to the case in which the addition rate has no effect on particle size (precipitation of lysozyme from DMSO16), and to that in which particle size decreases with QA, and at intermediate QA values bimodal distributions are obtained (precipitation of a proprietary organic compound from ethanol14,15). The present case, in which the average particle size decreases with the addition rate but no significant modification of the PSD is observed while changing QA, corresponds to the situation where secondary nucleation does not play a significant role and all particles are formed at a similar process time during a single major primary nucleation event. The analysis using the model has shown that



Figure 9. Effect of the initial saturation at T ) 25 °C, QA ) 0.6 min-1 and n ) 500 rpm. SEM photomicrograph of the microparticles precipitated in (a) run P22 at S0 ) 0.5; (b) run P23 at S0 ) 0.9.

Figure 10. Effect of the stirring rate on the average particle size at 25 °C, QA ) 0.6 min-1 and S0 ) 500 rpm.

nucleation occurs at different supersaturation levels for different values of the antisolvent addition rates.17 Larger QA values lead to higher supersaturation, hence to larger nucleation rates, which yield more particles that grow to a smaller final average size. Thus summarizing, these results indicate that the GAS recrystallization is a robust process that can be scaled up, i.e., the same product quality can be obtained in different experimental setups with different precipitator size and gas supply mode, provided the same operating conditions in terms of specific antisolvent addition rate are maintained. This confirms previous findings on a different organic compound.14,15 Moreover, the results demonstrate that the average particle size of paracetamol particles can be varied in a controlled way between about 250 and 50 µm, by changing the specific CO2 addition rate in a range spanning almost 2 orders of magnitude. This furthers supports the claim that this may be a powerful technique to tailor the size of organic microparticles.

3.2 Effect of Temperature. The effect of temperature was studied in the range between 5 and 40 °C, i.e., from subcritical to supercritical conditions. The amount of paracetamol dissolved in acetone was adjusted so as to maintain an initial solution saturation corresponding to 80% of the solubility value, and the stirrer speed was again kept constant at 500 rpm in all experiments considered here. In Figure 6, the average particle size of the product harvested in runs P16, P03, and P04, and P20 at QA ) 0.2 min-1 and in runs P19, P10, and P11, and P21 at QA ) 2 min-1 (all carried out in unit 1) is plotted against temperature. A trend leading to larger particles at higher temperature can be observed, particularly going from 25 to 40 °C. Decreasing the temperature to 5 °C seems to have a significant effect at low addition rate and a minor, if not opposite, one at high addition rate. However, it is worth noting that the experiments at T ) 5 °C in unit 1 (P16, P18, P19) lead to rather similar average particles size, namely, 120, 160, and 140 µm, whose trend though does not follow the expected decrease with increasing QA. The particles produced in runs P19 and P21 are shown in Figure 7. This highlights a feature of the results obtained at high addition rate, namely, that the predominant morphology is different in the different experiments, i.e., the tabular morphology c in run P19 at 5 °C, morphologies a or b in run P10 and P11 at 25 °C, and the more equant morphology b in run P21 at 40 °C. This makes of course the comparison of the mean particle size more difficult than in the case of the experiments at QA ) 0.2 min-1 where the prevailing morphology is always b. 3.3 Effect of Initial Solution Concentration. Let us now consider runs P22 and P23, together with runs P06 and P07, carried out varying the initial solution concentration between 50 and 90% of the solubility value, while keeping all the others parameters constant (T ) 25 °C, n ) 500 rpm, QA ) 0.6 min-1). The results are illustrated in Figure 8, where the average particle size is plotted as a function of the initial saturation, S0. The effect of S0 is clearly rather small, as confirmed also by the observations of the photomicrographs in Figure 9 (runs P22 and P23); it is certainly smaller than the effect of the antisolvent addition rate and of the tem-

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Figure 11. Effect of the stirring at 25 °C, QA ) 0.6 min-1 and S0 ) 0.8. SEM photomicrograph of the microparticles precipitated in (a) run P24 at n ) 150 rpm; (b) run P25 at n ) 1000 rpm.

perature. This is in full agreement with the experimental evidence on different compounds,14,16 and with the model results.17 3.4 Effect of the Stirring Rate. Let us finally consider runs P24 and P25, at a low and high stirring rate of 150 and 1000 rpm, respectively, together with the two runs P06 and P07 at the standard 500 rpm, all other conditions being the same. The average crystal size plotted in Figure 10 as a function of the stirring rate indicates a rather significant effect, whereby intensifying the stirring yields smaller particles. Stirring enhances mass transfer and CO2 absorption in the solution,18 thus allowing for higher supersaturation levels and nucleation rates, and hence smaller particles. Moreover, intense stirring causes more significant particle breakage, leading to a shift of the PSD to the left. The latter effect is confirmed by looking at the photomicrographs in Figure 11 where particles obtained in runs P24 and P25 are shown, and the presence of more small fragments in the product of the latter experiment is evident. 3.5 Morphology. It has recently been possible to clarify in which way and through which mechanism the macromorphology, i.e., the habit of monoclinic paracetamol crystals, is influenced by the degree of supersaturation and by the temperature at which particle formation occurs. Three morphologies have been highlighed, as discussed at the end of the introduction to section 3. All these have been observed in our experiments, as indicated in Table 1. Columnar crystals (type a) predominate in Figure 3 (run P06) and Figure 4 (run P10); more equant crystals (type b) are the majority in the photomicrographs of Figure 9 (runs P22 and P23). Tabular crystals of type c are predominant in Figure 7a (run P19). Carrying out crystallization at controlled, high supersaturation at 3 and 47 °C, tabular and more equant crystals, respectively, were obtained.7 In another report, it was shown that at 30 °C increasing the supersaturation, at which paracetamol was formed, allowed the formation of crystals with morphology from type a, to type b, and then to type c.21,23 These results were rationalized by showing that at 30 °C and at 47 °C the

growth rates of two faces depend on supersaturation rather differently, one being larger than the other at low supersaturation, and the opposite at high supersaturations.7,21,22 Such a cross over effect with supersaturation is not observed at 47 °C.7 Since in the gas antisolvent recrystallization one can choose the operating temperature and can control the supersaturation at which crystallization occurs through the antisolvent addition rate,17 it is possible to analyze particle morphologies obtained in this work in the light of the literature results. It is worth noting that all runs in unit 1 have been carried out using the same precautions to minimize the presence of impurities; hence, the results obtained in unit 1 should indeed reflect the effect on the crystal habit of T and QA only. With reference to Table 1, in general it can be observed that the macromorphologies obtained and the effects of T and QA are constant with the literature results. This is particularly evident in the series of experiments at 5 °C and increasing addition rate, i.e., runs P16, P18, and P19, in which particle morphology evolves from a more equant b, with some columnar crystals a at QA ) 0.6 min-1, to the tabular forms c at the highest addition rate. This is the same effect observed in ref 21 and studied theoretically in ref 22. At the highest temperature of our experiments, i.e., T ) 40 °C, runs P20 and P21, the same change of addition rates, hence of supersaturation does not lead to changes of the particle habit, which remains type b. Again, this is in good agreement with the results at 47 °C reported previously.7 The extensive series of runs at 25 °C with different QA values does not exhibit a clear trend in terms of morphology, the more equant crystal form b being the most predominant in all the experiments. It is however not inconsistent with the literature results that columnar crystals are observed almost always and are predominant only at relatively low addition rate (run P06), whereas some tabular crystals are observed only at the highest QA values of runs P10 and P13. A final remark regards the effect of the stirring rate. It is recognized that increasing the stirring rate n leads to faster mass transfer and to higher supersaturation


levels.18 In terms of morphology, therefore, increasing n should have the same effect as increasing the antisolvent addition rate. This is indeed the effect that can be observed by comparing run P24 at n ) 150 rpm, runs P06 and P07 at n ) 500 rpm, and run P25 at n ) 1000 rpm. In the first run, mostly columnar crystals are obtained. In the runs at n ) 500 rpm crystals of type a and b coexist. Finally, at the highest stirring rate only the more equant crystal of type b are observed. 4. Conclusions The gas antisolvent recrystallization of paracetamol from acetone using CO2 as antisolvent by the GAS process has been studied experimentally. This technique allows for a tight control of the supersaturation level at which nucleation of the solid phase takes place. When only one nucleation event occurs during the process, as in this case, the final number of particles is controlled by the nucleation rate, and hence by the corresponding supersaturation level. The final average particle size depends on the material balance, through the initial solute content and the number of particles produced. Such feature, which makes the gas antisolvent techniques so attractive, is demonstrated in this work in three ways. First, we could tune particle size between 50 and 250 µm by varying the specific CO2 addition rate over 2 orders of magnitude. On the contrary, the effects of temperature, initial concentration, and stirring rate were minor. Second, we have shown that very similar particles can be obtained in different setups, provided the same supersaturation level where nucleation occurs is attained. This is controlled by the specific antisolvent addition rate. Finally, we have observed that different operating conditions lead to different morphologies in a way that is consistent with the effect of supersaturation on morphology reported for recrystallization of paracetamol from solution. Our study proves that the specific antisolvent addition rate may be used to tune the final particle size as well as the particle morphology. Acknowledgment. The authors would like to thank Kurt Schafflu¨tzel (Novartis Pharma AG) for help in running the experiments in unit 2, and Markus Huber (ETH Zu¨rich) for help in performing SEM analysis. M.M. is thankful to Professor Piet Bennema for drawing his attention to a recent paper of his22 and to the effect discussed in section 3.5. Notation c [wt %] c.v. [-] M0 [g] Mflush [kg]

concentration coefficient of variation of the volume PSD initial amount of organic solvent amount of CO2 used in flushing step

Crystal Growth & Design, Vol. 4, No. 5, 2004 889 n [rpm] QA [min-1] S0 [-] T [°C] xjvol [µm]

stirring rate specific CO2 addition rate relative saturation temperature average particle size of the volume PSD

Greek symbols σ [µm]

standard deviation of the volume PSD

Abbreviations CO2 GAS PCA

carbon dioxide gas antisolvent (process) precipitation with compressed antisolvent particle size distribution scanning electron microscopy

PSD SEM

References (1) Subramaniam, B.; Rajewski, R.; Snavely, K. J. Pharm. Sci. 1997, 86, 885-890. (2) Jung, J.; Perrut, M. J. Supercrit. Fluids 2001, 20, 179-219. (3) Rogers, T.; Johnston, K.; Williams, R., III Drug Dev. Ind. Pharm. 2001, 27, 1003-1015. (4) Kompella, U.; Koushik, K. Crit. Rev. Ther. Drug Carrier Syst. 2001, 18, 173-199. (5) Thiering, R.; Dehghani, F.; Foster, N. J. Supercrit. Fluids 2001, 21, 159-177. (6) Granberg, R. A.; Rasmuson, C. R. J. Chem. Eng. Data 1999, 44, 1391-1395. (7) Shekunov, B.; Aulton, E. A.; Adama-Acquah, R. W.; Grant, D. J. W. J. Chem. Soc., Faraday Trans. 1996, 2, 439-444. (8) Shekunov, B.; Grant, D. J. W. J. Phys. Chem. B 1997, 101, 3973-3979. (9) Nichols, G.; Frampton, C. S. J. Pharm. Sci. 1998, 87, 684693. (10) Wubbolts, F. E. Supercritical Crystallization - Volatile Components as (Anti-)Solvents, Thesis, TU Delft, 2000. (11) Bristow, S.; Shekunov, T.; Shekunov, B.; York, P. J. Supercrit. Fluids 2001, 21, 257-271. (12) Shekunov, B.; Hanna, M.; York, P. J. Cryst. Growth 1999, 198/199, 1345-1351. (13) Shekunov, B.; Baldyga, J.; York, P. Chem. Eng. Sci. 2001, 56, 2421-2433. (14) Mu¨ller, M.; Meier, U.; Kessler, A.; Mazzotti, M. Ind. Eng. Chem. Res. 2000, 39, 2260-2268. (15) Muhrer, G.; Mazzotti, M.; Mu¨ller, M. J. Supercrit. Fluids 2003, 27, 195-203. (16) Muhrer, G.; Mazzotti, M. Biotechnol. Prog. 2003, 19, 549556. (17) Muhrer, G.; Lin, C.; Mazzotti, M. Ind. Eng. Chem. Res. 2002, 41, 3566-3579. (18) Lin, C.; Muhrer, G.; Mazzotti, M.; Subramaniam, B. Ind. Eng. Chem. Res. 2003, 42, 2171-2182. (19) Muhrer, G. Gas Antisolvent Recrystallization of Specialty Chemicals, Thesis, ETH Zurich, 2002. (20) Beyer, T.; Day, G. M.; Price, S. L. J. Am. Chem. Soc. 2001, 123, 5086-5094. (21) Ristic, R.; Finnie, S.; Sheen, D. B.; Sherwood, J. B. J. Phys. Chem. B 2001, 105, 9057-9066. (22) Boerrigter, S. X. M.; Cuppen, H. M.; Ristic, R. I.; Sherwood, J. N.; Bennema, P.; Meekes, H. Cryst. Growth Des. 2002, 2, 357-361. (23) Ristic, R., personal communication, 2003.

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Gas Antisolvent Recrystallization of Paracetamol from Acetone Using

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