Precipitation of Mandelic Acid with a Supercritical Antisolvent

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Ind. Eng. Chem. Res. 2007, 46, 1552-1562

Precipitation of Mandelic Acid with a Supercritical Antisolvent Process: Experimental and Theoretical Analysis, Optimization, and Scaleup A Ä ngel Martıń,* Laura Gutie´ rrez, Facundo Mattea, and Marıá Jose´ Cocero Departamento de Ingenierıá Quı´mica y Tecnologıá del Medio Ambiente, Facultad de Ciencias, UniVersidad de Valladolid, 47011 Valladolid, Spain

An experimental and theoretical analysis of the precipitation of mandelic acid with a semicontinuous supercritical antisolvent (SAS) process is presented. The experimental section comprises a study of the effect of different operating parameters on particle size, including pressure, temperature, solution concentration, and flow rates. Prismatic or needlelike particles with lengths of 30-200 µm have been obtained, with precipitation yields between 20% and 80%. The parameter with a stronger influence on particle size is temperature, while an increase in the initial concentration allows a large increase in the precipitation yield with small variations in particle size. Variations in the injection velocities in the nozzle had only a minor influence on particle size. In the theoretical section the application of a detailed mathematical model of the SAS process to this system is discussed. The model is used for the interpretation of the different experimental trends and to propose the optimum process parameters. The model is also used to study the scale-up of the process and particularly the design of the nozzle for higher flow rates. As experimentally it has been found that the parameters of the nozzle do not affect particle characteristics, this discussion is focused on the determination of the required precipitator volume for different nozzle designs. Finally, a scaled-up process with a 5-20 times increase in flow rates and product amount has been tested experimentally, obtaining results similar to those in the lower scale experiments. Introduction Since size, size distribution, and morphology of particles are of the utmost importance in pharmaceuticals, cosmetics, and other applications,1 particle design technologies have an increasing relevance. The supercritical antisolvent (SAS) processes for the production of fine powders have several advantages over other precipitation methods due to the peculiar properties of supercritical fluids: the mixing between the supercritical antisolvent and the liquid is much faster than in conventional liquid antisolvent processes, thus leading to higher supersaturations and smaller particle diameters. Moreover, it is possible to control the particle size distribution (PSD) with changes in the operating conditions. The supercritical antisolvent can be easily removed from the final product by reducing pressure, in contrast to the complex purification processes often required when organic antisolvents are used. With a proper selection of the antisolvent, it is possible to carry out the process at nearambient temperatures, avoiding the thermal degradation of the product. For these reasons supercritical antisolvent processes have been extensively studied in recent years for applications which include pharmaceuticals, natural compounds, explosives, polymers, and pigments.2-4 One of the main challenges in the development and optimization of an SAS process is the large number of process parameters that affect the performance of the process. Further, the interactions between these parameters due to their simultaneous influence on different process steps such as the fluid mechanics, mass transfer, and particle formation and growth kinetics make it difficult to relate changes in the process conditions to changes in product characteristics, or to predict the effect of a certain variation in the operating parameters. For this reason the development of an SAS process often requires an extensive * To whom correspondence should be addressed. Tel.: (+34) 983423-174. Fax: (+34) 983-423-013. E-mail: [email protected].

experimental study with different combinations of process parameters.5-7 Likewise, when an SAS process is scaled up, it is difficult to predict the effects of the variations in the process design on its performance, and particularly the variations in the fluid mechanics and mass transfer behavior of the process. There are very few references in the literature which deal with the scale-up of SAS processes. Some of the most representative are the papers of Reverchon et al.8 and Jarmer et al.9 In the first, the authors applied their results on the precipitation of amoxicillin in a laboratory scale5 to develop a precipitation process on a pilot scale. They found that the parameters that determine the product characteristics were the same in the laboratory scale and pilot scale. In particular, the initial concentration of the solution had a strong effect on the particle size and the PSD of the product. However, the design of the nozzle had a limited influence on the process, and although different nozzles were used in the laboratory- and pilot-scale experiments, product characteristics remained almost the same. In contrast, Jarmer et al.9 studied a case (the precipitation of poly(lactic acid)) in which the design of the nozzle had a strong influence on the performance of the process. These authors studied different criteria for scaling up the nozzle. They found that the best scale-up criterion was a constant energy dissipation rate in the nozzle, while maintaining a constant Reynolds number or axial velocity was not enough to ensure the reproducibility of the results. Those two papers illustrate which are the critical parameters of the process depending on the operating conditions and in particular on the position of the operating point with respect to the mixture critical point: the thermodynamic parameters above the mixture critical point, and the fluid mechanic parameters under conditions of partial miscibility. In a previous work,10 a mathematical model of the SAS process was developed. This model considers the main steps of the SAS process, including the fluid mechanics, the mass transfer, and the kinetics of particle nucleation and growth. One

10.1021/ie0608051 CCC: $37.00 © 2007 American Chemical Society Published on Web 02/08/2007

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of the main applications of this model is the possibility of obtaining a deeper insight into the interactions between the process steps and the way in which a variation in the process conditions affect each of them. The combination of this knowledge with an experimental study of the process can provide the basis for a rational optimization and scale-up of the process. In this work this approach has been applied to the development, optimization, and scale-up of the supercritical antisolvent precipitation of mandelic acid. Mandelic acid (or R-hydroxybenzeneacetic acid) is a hydrocarboxylic acid which is extracted through hydrolysis of the almond extract. It has been used in medicine for many years as a urinary antiseptic. It is also traditionally used in organic synthesis of drugs, dyes, and pesticides, and also as a resolving agent for chiral drugs.11 Over the past few years, mandelic acid has been studied extensively for its possible uses in treatment of common skin problems such as photoaging, irregular pigmentation, and acne, thanks to its antibacterial action and facial skin renovating activity.12 This substance has several characteristics that make it attractive as a model substance for the development of SAS processes: the physical properties required for the application of the mathematical model (temperature and heat of fusion, critical properties) can be measured or reliably estimated with group contribution methods due to the simple chemical structure of the molecule, while most pharmaceuticals undergo thermal degradation before reaching their melting points, or have complex chemical structures that limit the accuracy of estimation methods. As will be discussed later, the phase equilibrium of this substance in CO2, essential for the analysis of a precipitation process, is well-known. The substance is easy to handle and analyze, and it is not likely to undergo any degradation process that may affect the results. The precipitation of mandelic acid with other techniques is well studied, and comparison with results from those methods allows evaluation of the performance of the SAS process. Furthermore, for the applications of mandelic acid in the pharmaceutical and cosmetic industries, it is of interest to develop a process to obtain it as a fine powder. With the objective of developing an SAS precipitation process for mandelic acid, the effect of the operating parameters on product characteristics, including particle size, morphology, and precipitation yield, has been studied experimentally and was analyzed with the aid of the mathematical model. This information has been used to select the optimum operating parameters for this process. Finally, the scale-up of the process has been studied with the aid of the model, and the proposed scaled-up conditions have been tested experimentally. Experimental Section Materials. DL-Mandelic acid with a minimum purity of 99% was purchased from Fluka. Ethyl acetate with a minimum purity of 99.5% was purchased from Panreac Quı´mica (Spain). CO2 at 99.95% was delivered by Carburos Meta´licos S.A. (Spain). Equipment. A schematic diagram of the pilot plant used for the semicontinuous SAS process is presented in Figure 1. The precipitator is an isolated and jacketed AISI 316 stainless steel vessel of 1.5 L volume (inner diameter 10 cm, height 20 cm). A porous metallic frit with a screen size of 1 µm placed at the bottom of the precipitator is used to collect the particles. Two diaphragm pumps are used to feed the supercritical carbon dioxide (SC-CO2) and the organic solution to the vessel. These streams are mixed with a concentric tube nozzle placed at the top of the precipitation vessel. This nozzle consists of a capillary with an inner diameter of 100 µm for the solution and a

Figure 1. Schematic diagram of the SAS pilot plant (F, flow meter; T, temperature meter; P, pressure meter).

concentric 1/4 in. tube for CO2. The pressure in the precipitator is controlled with a needle valve, and pressure and temperature are measured by means of instruments connected to the precipitation vessel. After the depressurization the liquid organic solvent is collected and gaseous CO2 is discharged to the atmosphere. Procedure. A typical experiment starts by pumping pure CO2 into the precipitator. When the desired operating conditions (temperature, pressure, and flow rate) are achieved and remain stable, the solution (mandelic acid dissolved in ethyl acetate) is fed to the precipitator. When the desired amount of solution has been injected (approximately 300 mL), clean solvent is pumped in to sweep the solution retained in the inlet pipes (approximately 100 mL). This is necessary for an accurate determination of the precipitation yield, and additionally allows starting the next experiment injecting this clean solvent that is retained in the pipes of the solvent line, thus achieving steadystate solvent concentrations in the precipitator before the introduction of the solution. After this, the liquid pump is stopped and only pure CO2 is pumped in to dry the particles. After the decompression, a sample of the particles retained on the frit is collected for analysis. Samples of the feed and the liquid effluent collected after the depressurization step are also taken for analysis. More details about the experimental setup and the operating procedure can be found in previous works.13 Product Analysis. Pictures of the particles collected were taken by means of a Nikon OPTIPHOT-2 optic microscope and a scanning electron microscope (SEM) model JEOL JSM-820. The mean particle size was measured with Zeiss image analysis software. As the majority of the particles obtained in this work have prismatic or needlelike morphology, the values of particle size presented in this work correspond to the length of the needles. For the determination of the precipitation yield, the amount of mandelic acid precipitated is calculated as the difference between the amount of mandelic acid in the feed and the amount collected in the liquid effluent. To determine the concentration of mandelic acid in the effluent, a sample of known weight is taken; this sample is maintained at 60 °C for at least 3 days to eliminate the organic solvent. After drying, the mass of the solid residue is determined. Differential scanning calorimetry (DSC) analysis of the particles collected was performed with a DSC-30 Mettler apparatus, in the temperature range of -50 to 150 °C, with a heating rate of 10 °C/min and under nitrogen atmosphere. X-ray powder diffraction (XRPD) patterns were obtained using a Philips PW1710 apparatus with Cu KR radiation (40 kV, 30 mA). Experimental Results and Discussion Several experiments with different operating pressures, temperatures, initial concentrations, and flow rates have been

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Figure 2. Pictures of particles collected in some of the experiments of Table 1. Table 1. Summary of Experiments Performed expt

P (MPa)

T (K)

c0 (g/L)

S0

FCO2 (kg/h)

FSOL (kg/h)

yEA

d50 (µm)

Y (wt %)

comment

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 V1 V2 V3 S1 S2

9 9 9 9 9 8 10 11 9 9 9 9 9 9 9 9 9 9 9 10 10

323 323 308 313 333 308 308 308 323 323 323 323 323 323 323 323 323 323 323 333 333

40 40 40 40 40 40 40 40 30 50 75 40 40 40 40 40 40 40 40 70 70

0.50 0.50 0.50 0.50 0.50 0.50 0.50 0.50 0.38 0.63 0.92 0.50 0.50 0.50 0.50 0.50 0.50 0.50 0.50 0.86 0.86

2 2 2 2 2 2 2 2 2 2 2 1 2.5 3 2.5 1.5 2 2 2 10 10

0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.4 0.25 0.3 0.3 0.3 1 1

0.07 0.07 0.07 0.07 0.07 0.07 0.07 0.07 0.07 0.07 0.07 0.13 0.06 0.05 0.07 0.07 0.07 0.07 0.07 0.05 0.05

120 130 210 160 45 80 210 190 100 145 140 160 150 125 110 140 115 140 130 25 30

59 61 51 48 65 59 71 77 37 68 81 65 38 21 65 68 57 64 61 82 87

VPREC ) 0.7 L VPREC ) 1 L VPREC 1.5 L MMAND ) 30 g MMAND ) 120 g

performed in order to study the effect of these parameters on product characteristics. A summary of all the experiments is presented in Table 1. This table presents the operating temperature and pressure of each experiment (T and P), the initial concentration of mandelic acid in the ethyl acetate solution and the corresponding supersaturation (c0 and S0), the SC-CO2 and organic solution flow rates (FCO2 and FSOL), the composition of the fluid phase after complete mixing of those two streams in terms of the molar fraction of ethyl acetate in this fluid (yEA), the mean particle size obtained from the image analysis, corresponding to the length of the prisms or needles produced (d50), and the yield of the precipitation (Y). Figure 2 shows pictures of the particles collected from selected experiments, obtained with the optical microscope. It can be seen that in most experiments prismatic crystalline particles structure have been

obtained. The mean length of the particles is in the range of 20-200 µm. This is a large size compared to typical results of the SAS process. The reason for this could be the relatively high solubility of mandelic acid in CO2 (Figure 6) compared with the typically extremely low solubility of most substances precipitated with the SAS process. As particle formation rate grows exponentially with supersaturation,10 which in turn is inversely proportional to the solubility (S ) y/yeq), bigger particles are expected to be produced with more soluble substances. Nevertheless, it is a considerable reduction with respect to the size of the unprocessed particles, which are square plates with a side dimension of about 2 mm, and with respect to the particle sizes achieved with other crystallization techniques, which usually are in the range of 500-1000 µm.14,15


Figure 3. Variation of particle size and precipitation yield with temperature, corresponding to experiments 1-4 of Table 1 (P ) 9 MPa, c0 ) 40 g/L, yEA ) 0.07).

Figure 4. Variation of particle size and precipitation yield with initial concentration, corresponding to experiments 2 and 9-11 of Table 1 (P ) 9 MPa, T ) 323 K, yEA ) 0.07).

To check the reproducibility of the experimental results, two different experiments with the same operating conditions (experiments 1 and 2 of Table 1) were carried out. Similar results were obtained in both experiments, indicating that the reproducibility of the results is reasonably satisfactory considering the scale of the process. Of the different parameters investigated, the stronger influence on particle size is the temperature. The variations of particle size and yield with temperature in the temperature range of 308-333 K were investigated with experiments 2-5 of Table 1, and are presented in Figure 3. When the temperature was increased, a systematic decrease in particle size (from 210 to 45 µm) and an increase in the precipitation yield (from 50% to 65%) was observed. A likely reason for the particle size decresase is the decrease in the solubility of mandelic acid in CO2 with temperature at 9 MPa and with an ethyl acetate concentration of 0.07 (Figure 8; yEA ) 0.07 is the concentration of the fluid resulting from the complete mixing of the SC-CO2 and the solution flows), which results in a larger precipitation yield, and also in the larger supersaturation causing a smaller particle size. The effect of pressure was studied with experiments 6-8 of Table 1. Two different trends can be observed with respect to this parameter: in the pressure range 9-11 MPa, particle size shows no variations or a slight decrease with pressure, while the yield increases with pressure from 51% at 9 MPa to 77% at 11 MPa. However, when pressure is decreased from 9 to 8 MPa, a decrease in particle size and an increase in the precipitation yield is observed. The reason for this is that, at the lower pressure, the operating point lies below the mixture critical point (Figure 7) leading to a liquid-vapor phase split. The different precipitation mechanism in each of these regions explains the change in the influence of pressure. Figure 4 presents the variations in particle size and yield as a function of the initial concentration of the solution of mandelic

acid in ethyl acetate, corresponding to experiments 9-11 of Table 1. It can be seen that an increase in the concentration causes a slight increase in the particle size, from 100 µm for an initial concentration of 30 g/L to 140 µm for a concentration of 75 g/mL. The same variation in the concentration causes a large increase in the precipitation yield, from 37% to 81%. Yield is determined by the amount of mandelic acid that can be dissolved by the CO2. If the conditions of pressure, temperature, and flow rate are constant, the amount of solute dissolved by CO2 also remains constant, and therefore if more mandelic acid is fed to the precipitator, the precipitation yield must be higher. Figure 5 presents the results for different flow rates of carbon dioxide and organic solution. As presented in experiments 15 and 16 of Table 1, the two flow rates have been varied so as to maintain the solvent/CO2 ratio constant. This series of experiments allow the study of the possible variations in product characteristics caused by the variations in the fluid mechanic aspects of the process, and particularly in the performance of the mixing nozzle. The different flow rates tested in these experiments correspond to variations in the Reynolds number from 2000 to 4000 for the solution, and from 5000 to 10 000 in the case of CO2. When the flow rates are increased, the mean particle size decreases slightly (from 140 to 110 µm), while the precipitation yield remains constant. Since all the parameters which affect the phase equilibrium have not been varied in these experiments, a constant value of the precipitation yield could be expected. The slight reduction in particle size can be due to an improved performance of the mixing nozzle with higher flow rates. With experiments 12-14 of Table 1, a series of experiments with different CO2 flow rates and constant solution flow rates, and therefore with different solution/CO2 ratios, has been performed. The results of these experiments show that there is not a clear trend of variation of particle size with this parameter. With higher CO2 flow rates, a large decrease in the precipitation

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Figure 5. Variation of particle size and precipitation yield with solution flow rate at a constant solution/CO2 flow ratio, corresponding to experiments 2, 15, and 16 of Table 1 (P ) 9 MPa, T ) 323 K, c0 ) 40 g/L, yEA ) 0.07). Table 2. Pure Component Properties of Materials Considered in This Work component

Tc (K)

Pc (MPa)

ω

Tf (K)

∆Hf (J/mol)

carbon dioxide mandelic acid ethyl acetate

304.1 (ref 18) 903.8 (ref 19) 523.2 (ref 18)

7.38 (ref 18) 3.47 (ref 19) 3.83 (ref 18)

0.225 (ref 18) 0.645 (ref 19) 0.365 (ref 18)

394.5 (ref 20)

25600 (ref 20)

yield is also observed. The decrease in the yield is due to the simple fact that when the CO2 flow rate is increased, a larger amount of mandelic acid can be dissolved by the fluid. Finally, in another series of experiments, the residence time in the precipitator was varied by placing the filter at different heights inside the vessel (experiments V1-V3 of Table 1) and maintaining constant CO2 and solution flow rates. It can be seen that when the precipitator volume is reduced from 1.5 to 0.7 L, the results show almost no variation. This result is in agreement with the very short time scales of the precipitation process calculated in refs 6 and 10, and with the results of the fluid mechanic simulations that are presented in the Modeling section of this work. Therefore, it can be concluded that the volume of the precipitator is too large since a volume of less than 0.7 L would be enough for this process.

equilibrium in the ternary system CO2-ethyl acetate-mandelic acid. In this work, the Peng-Robinson cubic equation of state16 has been used for the description of the phase equilibrium. For the correlation of the solubility of mandelic acid in the fluid phase, the approach described by Shariati and Peters17 has been applied. Therefore, it is necessary to have information on the three binary subsystems (CO2-ethyl acetate, CO2-mandelic acid, and ethyl acetate-mandelic acid) for the calculation of the corresponding binary interaction parameters. The pure component properties considered for the modeling are summarized in Table 2.

Modeling The mathematical model developed in a previous work10 has been applied to the supercritical antisolvent precipitation of mandelic acid. This model allows the study of the effect of the different process parameters on the main steps of the precipitation, including the phase equilibrium, fluid mechanics, mass transfer, and particle nucleation and growth kinetics. The model is based on the differential mass and momentum conservation equations in the precipitator for a two-dimensional system with axial symmetry.

continuity:

(

mass: F Vr

∂ 1 ∂ (FVz) + (rFVr) ) 0 ∂z r ∂r

(1)

)

(2)

∂wa ∂wa 1 ∂ + Vz (rj ) + ra )∂r ∂z r ∂r ar

(

momentum: F Vr

) [ ( ( ))]

∂Vz ∂Vz ∂Vz 1 ∂ )rη + Vz ∂r ∂z r ∂r ∂r

Figure 6. Solubility of mandelic acid in SC-CO2: experimental data19 and correlation with the PR EoS.

(3)

For the resolution of the momentum conservation equations in turbulent flow, a k- turbulence model is used. For the calculation of the precipitation rate ra in eq 2, it is considered that particles are formed by primary nucleation, and grow by condensation and coagulation. The conservation equations are solved numerically with a finite difference scheme. Phase Equilibrium Modeling. For the application of the model it is necessary to have information of the phase

Figure 7. P-xy diagram of the ethyl acetate-CO2 system: experimental data21 and correlation with the PR EoS.

Ind. Eng. Chem. Res., Vol. 46, No. 5, 2007 1557 Table 3. Interaction Parameters system CO2-mandelic acid CO2-ethyl acetate ethyl acetate-mandelic acid

T (K)

kij

lij

308 318 328 303 313 323 308-328

0.0418 0.0268 0.0095 -0.150 -0.181 -0.147 0.009

0 0 0 -0.400 -0.333 -0.228 0

The results of the calculations for the binary systems are presented and compared to literature data in Figures 6 and 7. It can be seen that the agreement is satisfactory, with a mean deviation of 12% in the correlation of the solubility of mandelic acid in CO2, and of 0.8% in the calculation of bubble pressures of mixtures of CO2 and ethyl acetate. The interaction parameters calculated by correlating the literature data are presented in Table 3. With these parameters, it is possible to calculate the solubility of mandelic acid in mixtures of CO2 and ethyl acetate. The results for typical conditions for SAS experiments of 9 MPa and 308-323 K are presented in Figure 8 as a function of the composition of the fluid, ranging from yEA ) 0 (pure CO2) to yEA ) 1 (pure ethyl acetate). In this figure it is shown that in pure CO2 the solubility of mandelic acid decreases with temperature at a pressure of 9 MPa, as also presented in Figure 6. In contrast, the solubility in pure ethyl acetate is higher at higher temperatures. Therefore, there must be a point of intersection of the two isotherms, which in this case is located at a mole fraction of ethyl acetate of approximately 0.11. Solid-Fluid Interfacial Tension. The interfacial tension between the particles and the fluid is a parameter required for the application of the model.10 In the case of mandelic acid, this parameter has not been measured, nor can it be predicted. Therefore, a reasonable value must be assumed. The interfacial tension has a large influence on particle size, and higher interfacial tensions lead to slower nucleation rates and bigger particles. The value of this parameter can be calculated so that the calculated particle diameter matches the experimental results for certain operating conditions. The solid-fluid interfacial tension can then be assumed to be constant over the range of operating conditions of the experiments, thus allowing the prediction of the variations in particle size with different operating parameters. The main difficulty for the application of this approach to mandelic acid is that the model can only predict the formation of spherical particles, while needlelike particles are obtained in the experiments. Therefore, it is necessary to establish a way to compare the particle size with these different morphologies. In this work, it has been assumed that a spherical particle and a prismatic particle have an equivalent size when they are of the same volume. Of course, this is only a rough approximation, and it must be emphasized that the model yields only approximate values of particle size, and its applications are mainly the determination of the trends of variation and the reasons for these trends, not an exact prediction of particle size. With this approach, and assuming that the produced particles have a constant aspect ratio (length

Figure 8. Solubility of mandelic acid in the gas phase as a function of the concentration of ethyl acetate (P ) 9 MPa, T ) 308 and 323 K).

divided by width) of 5, the diameter of an equivalent sphere particle is obtained with the following equation:

dS ) 0.17d50

(4)

With this approximation, it has been established that the needlelike particles obtained in experiment 1 of Table 1 are approximately equivalent to spheres of 20 µm diameter. To obtain the same result with the model, the solid-fluid interfacial tension must have a value of σ ) 0.013 N/m. This is a reasonable value, which is in the same order of magnitude as some experimentally determined solid-fluid interfacial tensions.10 Model Results: Effect of Operating Parameters. The mathematical model has been used to perform an analysis of the effect of the different operating parameters, equivalent to the experimental analysis described in the Experimental Results section of this work. The results are presented in Table 4. The effect of both pressure and temperature (simulations 2 and 3) is explained by its influence on the phase equilibrium: an increase in pressure causes an increase in the solubility of mandelic acid in the gas phase. Therefore, lower supersaturations are achieved and bigger particles are obtained. Equally, a decrease in temperature at 9 MPa causes an increase in the solubility (Figure 8), with the same consequence: lower supersaturations and bigger particles. It is noticeable that, according to the simulations, the parameter with a stronger influence on particle size in the range of conditions considered in this work is temperature. The same conclusion was obtained with the experiments (Figure 3). The magnitude of the increase in particle size, of approximately 30 µm with a decrease in temperature from 323 to 313 K, is also similar in the simulations and the experiments. The variation of CO2 and solution flow rates, with a constant solution/CO2 ratio (simulation 6), represents the opposite situation. In this case, all the parameters which affect the phase equilibrium are maintained constant. The only effect of the increase in these flow rates is an improved mixing which leads to a negligible decrease in particle size. In the case of the initial concentration (simulation 4), this parameter affects both the nucleation, through the supersatura-

Table 4. Analysis of the Effect of the Operating Parameters: Summary of Simulations Performed simulation

P (MPa)

T (K)

c0 (g/L)

FCO2 (kg/h)

FSOL (kg/h)

dS (µm)

d50 (µm)

1 2 3 4 5 6

9 11 9 9 9 9

323 323 313 323 323 323

40 40 40 50 40 40

2 2 2 2 3 2.5

0.3 0.3 0.3 0.3 0.3 0.4

20.0 21.7 25.5 21.1 19.3 19.9

120 130 150 125 110 120

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Figure 9. Velocity and solvent concentration profiles calculated with the mathematical model for different nozzle configurations: (a) 1/16 in. solution tube-1/4 in. CO2 tube, conditions as in experiment 1 of Table 1; (b) 1/16 in. solution tube-1/4 in. CO2 tube, conditions as in experiment S2 of Table 1; (c) 1/ in. solution tube-1/ in. CO tube, conditions as in experiment S2 of Table 1 (plots with different color scales). 8 4 2

tion, and the particle growth kinetics, through the concentration of the solute in the fluid. Depending on which is the prevailing influence, an increase in the initial concentration can cause an increase or a decrease of particle size. In this case, according to the calculations, the increase in the particle growth rate with higher concentrations is the dominant effect, and therefore bigger particles are obtained with higher initial concentrations. This conclusion is in agreement with the experimental result. In the case of CO2 flow rate, according to the calculations, an increase of this flow rate causes a decrease in the mean

particle size. The most likely explanation is, once again, the variation of the solubility of mandelic acid in the fluid: with higher CO2/solution ratios, the concentration of solvent in the bulk fluid decreases and this solubility is lower, leading to higher supersaturations. Nevertheless, the magnitude of this reduction in particle size is small, in agreement with the unclear trend of variation of particle size with CO2 flow rate found in the experiments. It can be observed that except in the case of pressure, where the calculations show that bigger particles are produced at higher

Ind. Eng. Chem. Res., Vol. 46, No. 5, 2007 1559 Table 5. Characteristic Parameters of the Different Nozzle Configurations Studied configuration

dimensionsa

a b c

µm/1/

a

100 4 in. 100 µm/1/4 in. 1/8 in./1/4 in.

FSOL (kg/h) 0.3 1 1

FCO2 (kg/h) 2 10 10

Rea 3400/9100 8400/36 000 840/29 000

∆P(solution) (bar)

(solution) (m2/s3)

LMIX (mm)

1.1 7.0 0.01

7.0 × 1.1 × 106 0.1

35 71 29

104

Solution/SC-CO2.

pressures, while the opposite trend has been observed in the experiments, the model predicts correctly the trends of variation found experimentally with the different operating parameters. Optimization and Scaleup The information obtained with the experiments and the application of the model can be summarized as follows: (1) The particle size can be reduced by increasing temperature and decreasing pressure. (2) The operating pressure and temperature must be chosen so as to work in the region of complete miscibility between ethyl acetate and CO2 (Figure 7), as otherwise low precipitation yields are obtained. (3) If the initial concentration of the solution is increased, higher precipitation yields are achieved, with almost no variation in particle size. The maximum concentration of the solution is limited by the solubility of mandelic acid in ethyl acetate. (4) The best results in terms of particle size and precipitation yields are obtained with CO2/solution ratios in the range 6.510 kg/kg. (5) The inlet velocities of solution and CO2 have a small influence on the performance of the process. With this information, the following optimum operating conditions have been chosen: 10 MPa, 333 K, concentration of mandelic acid in the organic solution of 70 g/L, and CO2/ solution flow ratio of 10 kg/kg. Testing these conditions with the mathematical model, a mean particle size of dS ) 12 µm is obtained, representing a noticeable reduction in particle size. The selected optimum operating conditions have been tested experimentally. To study the scale-up of the process, different experiments with a 5-fold increase in the CO2 and solution flow rates, and a 20-fold increase in product amount, have been performed (experiments S1 and S2 of Table 1). As a previous step for these experiments, the performance of the nozzle with the increased flow rates has been studied with the aid of the mathematical model. Figure 9 presents the velocity and concentration profiles calculated with the model for different nozzle configurations and flow rates. The main parameters of the different nozzle configurations are presented in Table 5. These

parameters include the Reynolds number, the kinetic energy dissipation rate, obtained with the mathematical model, and the pressure drop in the nozzle, estimated with eq 5 for pressure

∆P )

FVz2 2

(5)

drop in orifices.22 These are the key parameters which characterize the fluidomechanic behavior of the nozzle.9 The last parameter of this table is the mixing length, defined as the precipitator length at which the solvent concentration at the center of the jet differs by less than a 5% from the bulk fluid solvent concentration. Case a of Figure 9 and Table 5 corresponds to the configuration of the nozzle used in experiments 1-16 of Table 1, with the operating conditions of experiment 1 of this table. The most noticeable result for this case is that the mixing length is just 35 mm. This is in agreement with the experimental results which indicate that the precipitator volume is oversized for this application. Case b corresponds to the behavior of this nozzle with the increased flow rates of experiments S1 and S2 of Table

Figure 11. DSC diagram of mandelic acid particles obtained in experiment S2 of Table 1.

Figure 10. SEM picture of particles obtained in experiment S2 of Table 1.

Figure 12. XRD diagram of mandelic acid particles obtained in experiment S2 of Table 1.

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Figure 13. Pictures of the precipitator and particles collected after experiment S2 of Table 1.

1. It can be seen that the higher injection velocity of the solution results in an increase of the mixing length up to 71 mm. Nevertheless, this length is still small enough to allow performance of the process in the same precipitator as the experiments with lower flow rates. However, the application of this configuration of the nozzle with the increased flow rates of experiments S1 and S2 presented the practical problem of an excessive pressure drop inside the solution capillary (estimated value22 0.23 MPa/mm). To solve this problem, and as the experimental results indicate that particle characteristics are insensitive to the parameters of the nozzle, the simplest solution has been applied, which is to substitute the 1/16 in. capillary by commercially available 1/8 in. tube (i.d. 1.6 mm). The results of the calculations with the model for this nozzle configuration are presented in case c of Figure 9 and Table 5. The mixing length for this configuration is only 29 mm, so once again the volume of the precipitation vessel used for the previous experiments is large enough for the experiments with increased flow rates. Additionally, the comparison of the results with nozzle configurations b and c allow the conclusion that, for a concentric tube nozzle operating in the complete miscibility region, it is more effective to increase the velocity of injection of CO2 through the concentric annulus than to increase the velocity of injection of the solution. With this nozzle configuration, the particles obtained in experiments S1 and S2 have properties very similar to those obtained in the experiments with lower flow rates: it can be seen in Figure 10 that the particles have the same prismatic morphology. The mean particle length is 30 µm, which is smaller than in any previous experiment but still is in the same range, in agreement with the calculations with the mathematical model. For a better characterization of the product, DSC and XRD analyses have been performed. The results for the particles collected in experiment S2 of Table 1 are presented in Figures 11 and 12. The temperature and heat of fusion obtained from the DSC analysis are 394.0 K and 26.0 kJ/mol, respectively, which are in good agreement with literature values of racemic mandelic acid (Table 3). The obtained XRPD spectrum matches literature values for racemic mandelic acid with orthorhombic crystalline structure. Pictures of the particles collected and the precipitator after experiment S2 are presented in Figure 13. With respect to the scale-up of the precipitation vessel and the nozzle, the experimental results allow the presentation of the following conclusions: (1) The increase in the flow rates causes a decrease in the residence time from approximately 65 s to 13 s. However, this reduction does not cause a noticeable variation in particle characteristics. Therefore, it would be possible to reduce the

residence time even more without a detrimental effect on the precipitation. Because of this, the precipitator volume will be determined not by the residence time needed for the precipitation, but by the technical requirements for the implementation of an efficient particle collection and retrieval system.23,24 (2) According to the different scale-up criterion presented by Jarmer et al.,9 the change in the nozzle dimensions in the higher flow rate experiments causes a variation in its performance. However, this does not affect product characteristics. This is in agreement with the results presented in the Modeling section, which show that the fluid mechanic aspects are of relatively secondary importance for this application, and with experimental results for systems operating in the same region of complete miscibility between SC-CO2 and solvent.4 Conclusions This work presents a rational methodology for the optimization and scaleup of supercritical antisolvent processes, based on complementary experimental and theoretical analyses. In the Experimental Results section, the influence of different operating parameters in the process has been studied. The particles produced have prismatic morphology in all the cases, with lengths between 30 and 200 µm. The main trends observed are as follows: (1) An increase in temperature causes a decrease in particle size and an increase in the precipitation yield. (2) With respect to pressure, in the pressure range 8-9 MPa different trends are observed than in the pressure range 9-12 MPa, indicating that there could be a change in the precipitation mechanism due to the operation in a different region. (3) An increase in the initial concentration of the solution has a slight effect on particle size, but causes a large increase in the precipitation yield. (4) An increase in the CO2 flow rate, maintaining constant the solution flow rate, causes a large decrease in the precipitation yield. The effect on particle size is not clear. (5) A variation of the solution and CO2 flow rates, maintaining the flow ratio constant, does not significantly affect the particle size or the precipitation yield. Next, the application of the SAS model to this process is presented. The model has been used to study the trends of variation of particle size with different operating parameters. It has been shown that the predicted trends agree with the experimental ones, and that the model allows obtaining a deeper knowledge of the reasons for these trends. With the experimental and theoretical information obtained from the previous analysis, the optimum operating conditions


for this process can be selected. In the case of the precipitation of mandelic acid, the parameters with a stronger influence on particle characteristics are pressure and temperature, and therefore the combination of these parameters that yields the smaller particle size has been selected. The CO2/solution flow ratio and the initial solution concentration are important parameters for the economy of the process. The initial concentration should be as high as possible, and the CO2 flow rate as low as possible, in order to maximize the throughput of the process. The design of the nozzle is of comparatively secondary importance to the operating conditions of this process, and a simple and robust design such a concentric tube nozzle is the best choice in this case. To study the scale-up of the process, the proposed optimum conditions have been tested with a 5-fold increase in the flow rates. To determine if the residence time in the precipitator was enough for the experiments with higher flow rates, several experiments with reduced precipitator volumes have been performed. It has been found that, even if the precipitator volume is reduced by one-half, no variation in particle characteristics is observed, indicating that the residence time could be decreased even more without a detrimental effect on the precipitation. This is due to the extremely short time scale in which the precipitation takes place, and it is in agreement with the predictions with the mathematical model of the required precipitator lengths for a complete mixing between solution and SC-CO2. It can be concluded that the precipitator volume is determined not by the requirements of the precipitation process, but by technical issues for an efficient collection of the particles. To avoid an excessive pressure drop in the nozzle, the capillary used for the lower flow rate experiments was replaced by a standard tube. This causes a large decrease in the energy dissipation rate in the nozzle. Nevertheless, the particles obtained in the scaled-up experiments have properties very similar to those obtained in previous experiments. This is additional proof of the relatively small influence of nozzle characteristics on the performance of the process. The operation in a region in which product characteristics are mainly determined by temperature, pressure, and composition, which can be easily maintained during the scale-up, and not by fluid mechanic aspects whose scale-up is less straightforward, greatly simplifies the scale-up process. Therefore, the operation under such conditions should be preferred whenever the phase equilibrium properties of the system allow it. Acknowledgment The authors thank VITATENE Leoń (Spain) for their technical and financial support. This work was partially financed by the Spanish Ministry of Science and Technology, PPQ 200307209, and by the EU Marie Curie ERT EPSS 007767 PROBIOMAT project. Nomenclature c0 ) solution concentration (g/L) cEA ) concentration of ethyl acetate (mass fraction) cMAND ) concentration of mandelic acid (mass fraction) d ) tube diameter (m) d50 ) particle mean size (µm) dS ) diameter of an equivalent spherical particle (µm) MCO2 ) amount of CO2 (kg) MMAND ) amount of mandelic acid (kg) FCO2 ) CO2 flow rate (kg/h) FSOL ) solution flow rate (kg/h)

∆Hf ) enthalpy of fusion (J/mol) j ) diffusion rate (kg/(m2‚s)) kij ) binary interaction parameter, Peng-Robinson EoS lij ) binary interaction parameter, Peng-Robinson EoS LMIX ) mixing length (mm) P ) pressure (MPa) ∆P ) pressure drop (MPa) Pc ) critical pressure (MPa) r ) precipitation rate (kg/(m3‚s)) Re ) Reynolds number ) dVzF/η S ) supersaturation ) y/yeq T ) temperature (K) Tc ) critical temperature (K) Tf ) melting temperature (K) Vr ) velocity, radial direction (m/s) Vz ) velocity, axial direction (m/s) VPREC ) precipitator volume (L) VSOL ) amount of solution (mL) w ) mass fraction x ) liquid molar fraction y ) gas molar fraction yEA ) concentration of ethyl acetate in the fluid after complete mixing of SC-CO2/solution flows (molar fraction) z ) axial coordinate Y ) precipitation yield (wt %) Greek Letters ) turbulent kinetic energy dissipation rate (m2/s3) η ) viscosity (Pa‚s) F ) density (kg/m3) σ ) solid-fluid interfacial tension (N/m) ω ) acentric factor Literature Cited (1) Shekunov, B. Y.; York, P. Crystallization processes in pharmaceutical technology and drug delivery design. J. Cryst. Growth 2000, 211, 122. (2) Shariati, A.; Peters, C. J. Recent developments in particle design using supercritical fluids. Curr. Opin. Solid State Mater. Sci. 2003, 7 (45), 371. (3) Jung, J.; Perrut, M. Particle design using supercritical fluids: Literature and patent survey. J. Supercrit. Fluids 2001, 20 (3), 179. (4) Reverchon, E. Supercritical antisolvent precipitation of micro- and nano-particles. J. Supercrit. Fluids 1999, 15 (1), 1. (5) Reverchon, E.; Della Porta, G.; Falivene, M. G. Process parameters and morphology in amoxicillin micro and submicro particles generation by supercritical antisolvent precipitation. J. Supercrit. Fluids 2000, 17 (3), 239. (6) Lengsfeld, C. S.; Delplanque, J. P.; Barocas, V. H.; Randolph, T. W. Mechanism Governing Microparticle Morphology during Precipitation by a Compressed Antisolvent: Atomization vs Nucleation and Growth. J. Phys. Chem. B 2000, 104, 2725. (7) Wubbolts, F. E.; Bruinsma, O. S. L.; van Rosmalen, G. M. Dryspraying of ascorbic acid or acetaminophen solutions with supercritical carbon dioxide. J. Cryst. Growth. 1999, 198/199, 767. (8) Reverchon, E.; De Marco, I.; Caputo, G.; Della Porta, G. Pilot scale micronization of amoxicillin by supercritical antisolvent precipitation. J Supercrit. Fluids 2003, 26 (1), 1. (9) Jarmer, D. J.; Lengsfeld, C. S.; Randolph, T. W. Scale-up criteria for an injector with a confined mixing chamber during precipitation with a compressed-fluid antisolvent. J. Supercrit. Fluids 2006, 37 (2), 242. (10) Martıń, A.; Cocero, M. J. Numerical modeling of jet hydrodynamics, mass transfer and crystallization kinetics in the supercritical antisolvent (SAS) process. J. Supercrit. Fluids 2004, 32 (1-3), 203. (11) Zingg, S. P.; Arnet, E. M.; McPhail, A. T.; Bothner-By, A. A.; Gilkerson, W. R. Chiral discrimination in the structures and energetics of association of stereoisomeric salts of mandelic acid with .alpha.-phenylethylamine, ephedrine, and pseudoephedrine. J. Am. Chem. Soc. 1988, 110 (5), 1565. (12) Yu, R. J.; Van Scott, E. J. Alpha-hydroxyacids and carboxylic acids. J. Cosmet. Dermatol. 2004, 3 (2), 76.

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(20) Lorenz, H.; Sapoundjiev, D.; Seidel-Morgenstern, A. Enantiomeric Mandelic Acid System-Melting Point Phase Diagram and Solubility in Water. J. Chem. Eng. Data 2002, 47 (5), 1280. (21) Wagner, Z.; Pavlicek, J. Vapor-liquid equilibrium in the carbon dioxide-ethyl acetate system at high pressure. Fluid Phase Equilib. 1994, 97, 119. (22) Coulson, J. M.; Richardson, J. F.; Backhurst, J. R.; Harker, J. H. Coulson and Richardson’s Chemical Engineering, 6th Edition; ButterworthHeinemann: Woburn, MA, 1999; Vol. 1. (23) Vemavarapu, C.; Mollan, M. J.; Lodaya, M. Needham, T. E. Design and process aspects of laboratory scale SCF particle formation systems. Int. J. Pharm. 2005, 292 (1-2), 1. (24) Perrut, M.; Clavier, J.-Y. Supercritical Fluid Formulation: Process Choice and Scale-up. Ind. Eng. Chem. Res. 2003, 42, 6375.

ReceiVed for reView June 23, 2006 ReVised manuscript receiVed December 18, 2006 Accepted January 9, 2007 IE0608051

Precipitation of Mandelic Acid with a Supercritical Antisolvent

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