Powder Micronization Using a CO2 Supercritical

Ind. Eng. Chem. Res. 2009, 48, 5671–5678

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MATERIALS AND INTERFACES Powder Micronization Using a CO2 Supercritical Antisolvent Type Process: Comparison of Different Introduction Devices Olivier Boutin,* Thomas Petit-Gas, and Elisabeth Badens Aix Marseille UniVersite´s, UMR-CNRS 6181, Mode´lisation, Me´canique et Proce´de´s Propres, Europoˆle de l’Arbois BP 80 13545 Aix en ProVence Cedex 4 France

Many recrystallization processes in supercritical medium utilize CO2 as antisolvent. This work presents two introduction devices based on the principle of the supercritical antisolvent process: the impinging jets and the concentric tube antisolvent reactor. Those two processes are very simple to develop and allow improving the mixing between the two phases. Some experiments have been conducted for the impinging jets using L-polylactic acid at 10 MPa and 308 K giving spherical particles with average diameter varying from 1.4 to 2.3 µm. For the concentric tube antisolvent reactor, griseofulvin was tested at 10 MPa and temperatures between 308 and 323 K providing needles with lengths between 25 and 50 µm. These results combined with previous ones allow comparing these introduction devices with the classical supercritical antisolvent (SAS) process, demonstrating the following improvements: (i) reduction of particle size, (ii) increase in initial solute concentration, and (iii) process intensification. Introduction Milling and classical crystallization in solution using organic solvents are some of the classical processes for nano- or micropowder generation. Some of these processes present drawbacks due to mechanical or thermal actions that can degrade the material. It is also usual to measure important organic solvent traces in the final powder leading to potential toxicity. The use of supercritical CO2 (SCO2) is an interesting alternative to recrystallize a solid, particularly in pharmaceutical applications. Usually, the purpose of such processes is to control particle size (PS), particle size distribution (PSD), and habit in order to set an interesting specific surface area and biodisponibility for pharmaceutical molecules. A good flowability and a high apparent density are also frequently expected. In some cases, the polymorphic control is also an important issue. Initially, a brief description of SCO2 properties and linked processes is necessary. Pure CO2 becomes supercritical at pressures higher than 7.38 MPa and at temperatures higher than 304.2 K. Its physical properties are regular for a supercritical fluid: high and tunable specific density (between 0.3 and 1 or higher), diffusivity ten times higher than that of water at normal conditions, and viscosity comparable to those of gases.1 These properties are very interesting for particles generation processes. Many systems have been elaborated with SCO2 playing the role of antisolvent such as1 ASES (aerosol solvent extraction system), PCA (precipitation with a compressed antisolvent), or GAS (gas antisolvent). For a good understanding of following discussions, Table 1 exposes the antisolvent processes and describes the mode of contact of the different phases. The processes exploited in this work lay out some similarities to the supercritical antisolvent (SAS) process. In this kind of process, the solid to be recrystallized is dissolved in an organic solvent. This solution is then sprayed out through a capillary or a nozzle in a SCO2 continuum that contains a certain quantity of organic solvent coming from the same capillary injection. The dispersion raises * To whom correspondence should be addressed. E-mail: [email protected]. Phone: (+33) 442 90 85 12.

small entities in which matter exchanges occur (solvent evaporation and CO2 blending). Depending on the operating conditions, the tension of surface between the two phases tends to zero; furthermore, expanding gaseous plumes are formed during the dispersion of the organic solution. This leads to a local variation of the solvent power inducing the solute supersaturation and its crystallization. The particles obtained are collected inside the vessel on a frit filter placed at the exit. A depressurization valve is placed at the exit in order to come back to atmospheric pressure. CO2 can be recycled for industrial application. These processes allow very interesting results mainly for the recrystallization of pharmaceutical molecules, like carbamazepine2 or sulfathiazole.3 They can also be employed for the coprecipitation of a molecule and an excipient, the two compounds being dissolved in the same organic solvent. These processes use organic solvent, but in small quantities. Furthermore, the residual traces are usually far below the toxicity limits (usually between a few parts per million and 0.5 wt %), and the separation and recovery of the solvent at the exit of the vessel is easily obtained by CO2 depressurization to gas at atmospheric pressure. The different processes presented in Table 1 can have different modes for the flows: cocurrent (SAS) or countercurrent (ASES), in a transitory state (PCA and GAS). The most interesting point is the way to improve the mixing between the phases. In some cases, the introduction device has been modified in comparison with the classical SAS process: employ of a vibrating element (SAS-EM); use of a co- or triaxial nozzle (SEDS); or use of a second fluid to enhance the dispersion (SAA, SFED). One way to improve the process is hence to use different introduction devices, which is the purpose of this work. For a good understanding of the local phenomena occurring in the process, it is interesting to make a comparison with processes based on crystallization in solution. Classical routes consist in varying one parameter of the system (temperature, concentration) in order to reach the solute supersaturation, leading to the formation of nuclei (nucleation) and their development (growth). It is important to notice that there are two kinds of nucleation: (i)

10.1021/ie8017803 CCC: $40.75  2009 American Chemical Society Published on Web 05/11/2009

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Ind. Eng. Chem. Res., Vol. 48, No. 12, 2009

Table 1. Introduction Devices Used in Different Supercritical Antisolvent Processes process SAS

name supercritical antisolvent

SAS-EM supercritical antisolvent enhanced mass transfer ASES

aerosol solvent extraction system

GAS

gas antisolvent

SAA

supercritical assisted atomization

SEDS

solution enhanced dispersion by supercritical fluids

PCA

precipitation with a compressed fluid antisolvent

SFED

supercritical fluid expansion depressurization

description This process is one of the first used for recrystallization in a supercritical fluid. The organic solution is simply introduced through the intermediate of a capillary. The solution jet is here deflected by a surface vibrating at an ultrasound frequency. This system is very close to the SAS technique and use a nozzle for the introduction of the organic solution and a counter current mode. An organic solution with the solute dissolved in an appropriate organic solvent is placed in autoclave. The supercritical fluid is then slowly added until the saturation is reached. It is conducted in transitory state. The supercritical CO2 is first solubilized in the organic solution. The solution is then sprayed in the precipitator where the evaporation of the liquid droplets is assisted with a N2 flow. This system is close to the SAS technique and uses a coaxial (or triaxial) nozzle for the introduction of the organic solution, the supercritical fluid (and water sometimes). The principle is the same as the SAS one, but the crystallization occurs in a batch manner, with a short injection of the organic solution. This process is very close to SAA, the N2 flux being heated.

Primary nucleation, in which crystals formation does not involve existing crystals of the same species. Primary nucleation can be homogeneous or heterogeneous. In the latter, an exogenous solid matter plays a role of an initiator. (ii) Secondary nucleation, which occurs with existing solute crystals. In the case of processes using CO2 as antisolvent, the key parameters are the following: supersaturation reached by the combined action of the antisolvent diffusion and organic solvent evaporation followed by nucleation. This step occurs not in the whole vessel but in very specific entities within the dispersion. More accurately, it is likely that the entities resulting from the dispersion have a small volume and that homogeneous nucleation occurs. In conclusion, the particularity of this process is that the primary nucleation could occur very locally inside the dispersion. The influence of operating conditions is now rather well-known for supercritical antisolvent processes. An increase of pressure allows, first of all, one to be sure that the system is under supercritical conditions, as working in a biphasic system can present some drawbacks.4 It has also been shown that an increase of pressure can also increase the mass transfer and hence the frequency of nucleation.5 The temperature also has an influence on the state (biphasic or supercritical) of the system. Some results also indicate

that an increase of temperature can increase or decrease particle size, depending on the system studied.6,7 The molar ratio between the organic solvent and the CO2 is also of a primary importance in understanding this process. If the organic solution flow rate is constant, an increase of this ratio leads to an increase of particle size. In that case, the concentration gradient between the two phases is less important, leading to worse mass transfer and a decrease of the nucleation frequency.6,7 The last important parameter is the initial concentration of solute in the organic solution. It is now well-know that in most cases an increase of this concentration leads to an increase of particle size. This is explained by Reverchon et al.6 by the fact that if the concentration is increased, the supersaturation occurs faster and hence the nucleation frequency decreases, allowing a more important crystal growth. To conclude, among the different parameters previously presented, the injection device or contacting device between the two phases (supercritical fluid and organic solution) plays a very important role. The classical injection device used in SAS processes is made of a capillary or a nozzle, positioned in a very large vessel filled with SCO2. At the injection, it is very important to control the mixing and the energy dissipated in order to ensure a good yield and reproducibility of the crystallization. This role of the device leads one to study different structures for the CO2 and organic solution introduction in order to obtain different contacting systems that could enhance the result of the process. Many devices exist (see Table 1), but they are sometimes difficult to process and present some reproducibility or scaling drawbacks. Two other systems have been developed and used in this work: (i) the concentric tube antisolvent reactor (CTAR) and (ii) the impinging jets technology (IT). Previous results have been obtained with the CTAR for the recrystallization of L-polylactic acid (LPLA)8 and with the IT for the recrystallization of griseofulvine.9 The purpose of this work is to present some results obtained for the CTAR with griseofulvin and for the IT with LPLA. These results allow comparing the performance of those two systems with the results obtained in classical SAS processes. Material and Methods Materials. The following components have been used for the experimental work: • CO2 (purity 99.5%) purchased from Air Liquid company (Paris, France) • acetone (analytic purity 99.8%) from Fluka Company (Buchs, Switzerland) • methylene chloride (purity 99.8%) purchased from Carlo Ebra-Sds (Val de Reuil, France) • L-polylactic acid (LPLA) purchased from Galactic Laboratories (France). L-PLA is a biopolymer used as a drug excipient in the pharmaceutical industry. • Griseofulvin (purity 98.8%) supplied by BIM SIFRAM GROUP (China). Griseofulvin (GF) has two polymorphic forms. Its chemical formula is C17H17ClO6. GF has a low solubility in water due to its hydrophobic groups (15 µg · mL-1 at 37 °C) but is rather soluble in many organic solvents such as methylene chloride, acetone, ethanol, tetrahydrofurane, or dimethylsulfoxide. These solvents are widely used in organic synthesis, in particular for pharmaceutical applications and do not represent any hazard for the human body if the limiting rate of residual solvent authorized within the tablets is respected. Particle Characterization. For the griseofulvin particles, the estimation of the particle size for each samples was carried out by means of an optical microscope MOTIC B2 (Motic Wetzlar, Germany) equipped with a digital camera. For the LPLA


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Figure 1. Experimental apparatus used for the impinging jets experiments (IT) and for the concentric tube antisolvent reactor (CTAR).

particles, some observations were carried out with a Hitachi S-3000 scanning electron microscope (Hitachi, Japan). Each sample was passed in a SC7620 sputter coater (Quorum Technologies, England) depositing a very fine layer (2 nm) of gold and palladium in order to optimize the frame resolution. The particle size as well as their standard deviation and particle size distribution (PSD) were obtained through at least 500 measurements taken from photographs. The images analysis was done using ImagJ software (1.38, National Institutes of Health, USA). The PSD were best fitted using a log-normal distribution, providing a good representation of the nonsymmetrical distribution. They were obtained using Origin Pro software (7.5, OriginLab Corporation). The XRD analysis was carried out with a Philips Pw-3710 diffractometer (Philips, Netherlands). Sample powders were placed on an aluminum sample holder. Samples were scanned over the range of 5.0-50.0° (2θ) with a step size of 0.050° (2θ) and a count time of 2.5 s per step. A Co KR source was used with a wavelength of 1.788 96 Å. This analysis concerns only griseofulvin. For griseofulvin experiments, the residual organic solvent rates have been measured. The organic solvents used in pharmaceutical industry are classified according to three groups depending on the maximum authorized concentration in the final product.28 For the two organic solvents used, methylene chloride is classified in group 2 (maximum residual solvent rate: 600 ppm), and acetone, in group 3 (maximum 5000 ppm). The residual contents have been analyzed by gas chromatography. The sample is dissolved in dimethyl sulfoxide (for the experiments conducted with acetone) or in acetone (for the experiments conducted with methylene chloride). The apparatus is a Chrompack CP 9001 equipped with a capillary column SGE BPX-624 and a flame ionization detector. For each solvent, an external calibration has been adjusted first. A straight line with a proportionality coefficient named K gives the relation between the area of a peak (A) and the mass of residual organic solvent (mS in grams): mS ) KA

(1)

The K values are the following (with the correlation coefficient): 3 × 10-11 (0.999) for dimethylsulfoxide, 1 × 10-12 (0.997) for

acetone, and 2 × 10-11 (0.992) for ethylene chloride. The solvent mass mSC (g) in the calibration solution is given by mSC )

FSViωSC 100

(2)

where FS stands for density of the calibrated solution which depends on the organic solvent used (g · mL-1), Vi stands for the injected volume (4× 10-3 mL), and ωSC is for the solvent mass content in the calibrated solution (%). It is possible to calculate the residual solvent mass concentration in griseofulvin CSR (ppm) by CSR )

100mS × 106 ViFSωG

(3)

where ωG stands for the massic content of griseofulvin dissolved in the solvent used for the analysis (%). Experimental Devices. Figure 1 shows the common area for the two processes and each particular zone of the CTAR and the IT system. For the common part, supplying lines with pumps and heating systems allow introducing the CO2 and the organic solution at the desired pressure and temperature. At the exit of the systems, a metallic frit filter (pore size 2 µm) is placed in order to keep the particles inside the system. After this filter, a depressurization valve is placed in order to depressurize the flux and to recover the organic solution in a cold trap. In the laboratory experimental system, CO2 is not recycled. Its flow rate is measured at atmospheric pressure using a ball flowmeter. This part is the same as all supercritical antisolvent systems, which are, for instance, described in the work of Charbit et al.1 Figure 1 also represents the particularity of the introduction devices utilized in this study. Concerning the CTAR, the organic solution is introduced through a capillary placed inside a small tube (1/2 in.). In this tube, the SCO2 flow is introduced. More detailed information on this system can be found in the work of Boutin et al.8 Concerning the IT system, two capillaries are employed: one for the organic solution and the other for the SCO2. Those two capillaries are positioned face to face, at a distance of 8 × 10-3 m. They are placed in a large vessel (760 mL) where a SCO2 continuum flows in order to control the global molar ratio

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Table 2. Literature Results for the Micronization of Griseofulvin and LPLA process

solventa

SAS ASES GAS SAS-EM SAA SFED

DMSO, MC Ac, Eth, DMF Ac THF, MC Ac Ac + Eth

SAS GAS PCA PCA SEDS PCA SAS

MC/Chlo MC MC MC + Ac MC MC MC

pressure (MPa)

temperature (K)

internal diameter (capillary or nozzle) (µm)

15 5.2-19 10 9.6 7-9 8

313 283-333 343 308 343-363 333

60 50-250

8.0-10.0 5.5-9.7 8.2 13-18 8.5-17 8.5 8.4-9

308 304-313 305 308-313 302-333 308 313-323

solvent/CO2 molar ratio (%)

solute conc (wt %)

size (µm)

ref

griseofulvin 5 4

75 80 150

1.6 0.7-10 0.4 0.4-2 0.8

few mm few mm 125 µm-20 mm 0.1-0.5 0.5-3 0.5-0.7

10 11 12 13 14 15

0.5-3 0.6-1 1-3 2.3 1.52-2.27 0.12-0.25 1

1-7 0.5-3.1 1-5 0.5-7.9 3.3-25.7 0.7-1 0.2-5.5

16-18 19 20 21, 22 23 24 25

L-polylactic acid

a

150-500 75 100

5-10 0.4-0.9 2-4 4

350-700 100-252 100

DMSO dimethylsulfoxide; MC methylene chloride; Ac acetone; Eth ethanol; DMF dimethylformamide; THF tetrahydrofuran; Chlo chloroform.

Table 3. Experimental Results for the Micronization of Griseofulvin Using the CTAR Systema

a

run

temperature (K)

capillary internal diameter (µm)

solventb

organic solvent/CO2 molar ratio (%)

griseofulvin concentration (wt %)

1 2 3 4 5 6 7 8

308 308 308 308 308 308 318 323

500 500 500 500 500 128 128 128

acetone MC MC MC MC MC MC MC

2.4 5 1.5 8 10 4 4.5 6.5

4 2 10 10 10 10 10 10

size (µm) 50.3 25.1 30.2 40.4 50.9 26.1 27.7 34.2

( ( ( ( ( ( ( (

18.5 12.3 8.2 13.4 17.4 7.9 9.0 11.0

Pressure 10 MPa; CO2 flow rate 600 g · h-1. b MC methylene chloride.

(organic solvent/CO2). A detailed description on this system can be found in the work of Calvignac and Boutin.9 Results Results Obtained for the Micronization of Griseofulvin Employing the CTAR System. In order to examine CTAR performance, it is important to discuss previous results achieved on griseofulvin recrystallization with other SAS systems. Some examples are listed in Table 2. The first three examples concern classical processes: SAS, ASES, and GAS. All the crystals obtained have an acicular habit, with large needle lengths, between 125 µm and a few millimeters. Then, those processes do not present interesting results in terms of particle size. More sophisticated processes have been tested: SAS-EM, SAA, and SFED (see Table 1). They are made up of more advanced introduction devices and/or need more energy. The informations given in Table 2 indicate that the average particle size is significantly reduced, between 0.1 and 3 µm. These systems are necessary to reduce the griseofulvin particle size; however, they have many drawbacks. For instance, they are complex to process and they require more energy. CTAR has been tested in this work for the micronization of griseofulvin. It is different from a classical SAS and very easy to process. Some of it advantages are the following:8 simple processing and good mixing and dispersion. In this part, the working pressure is always 10 MPa. Temperature varied between 308 and 313 K, and two solvents have been tested: acetone and methylene chloride. The pressure and temperature have been chosen in the classical field of SAS processes. At the studied temperatures and at a pressure of 10 MPa, the solvent and CO2 binary systems are above the critical pressure of the mixture: roughly 8.5 MPa for methylene chloride26 and 8 MPa for acetone.27 Two capillary diameters have been used: 128 and

500 µm. The griseofulvin mass concentration in the initial organic solution varies between 2 and 10%, and the molar ratio solvent/CO2 varies between 1.5 and 10%. This ratio is the ratio of the solvent molar flow rate upon the CO2 molar flow rate. Those values have been chosen in order to investigate a large domain. The results are given in Table 3. Runs 3 and 5 have been repeated (three times) in order to test the reproducibility of the experiments. Concerning the X-ray diffraction analysis, a comparison between the patterns obtained for run 3 and the pattern for the commercial griseofulvin (see Figure 2) indicates that the polymorphic form was not changed by the process. This result is the same for all runs. All crystals exhibit an acicular habit. The residual organic solvent content has been measured for all samples. The values are always far lower than the authorized limit by the pharmaceutical industry, indicating a good powder quality for this parameter. The needle lengths are between 25 and 50 µm depending on the experimental conditions. The results of this work are midway with respect to those presented in Table 2. The needle lengths are higher than those obtained with a more sophisticated introduction device but smaller than those obtained with classical SAS processes, with values of a few millimeters. Even if the size reduction is not completely successful, it is possible to reduce significantly the particle size with the CTAR. Due to the simplicity of the CTAR, this result is very interesting to consider. This reduction is due to the influence of the hydrodynamics of the organic solvent jet and SCO2 flow. As the SCO2 surrounds the organic solvent jet at high speed in a confined place, the mixing is thus improved. In this way, supersaturation is obtained very quickly, leading to an increase of nucleation frequency and a decrease of crystal growth.


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Figure 2. X-ray diffraction pattern of griseofulvin before (plain line) and after micronization (dotted line).

Then, it is possible to study the influence of different operating parameters. The influence of the organic solvent is not specific to our system as it is not a hydrodynamic parameter. What is more, the comparison is inaccurate since griseofulvin solubility is quite different in the two solvents (5 wt % in acetone and 15 wt % in methylene chloride, T ) 20 °C). However, it seems that the influence of the solvent is rather irrelevant while the needle lengths obtained with acetone (50 µm) and those obtained with methylene chloride are roughly the same. Then, it appears that an increase of the molar ration (organic solvent/CO2) leads to an increase of the average particle size (runs 3-5) for a capillary diameter of 500 µm. This effect is important, as needle length is multiplied by 1.7. This effect is also known in classical SAS processes. The increase of the organic solvent in comparison with CO2 leads to a higher organic solvent concentration in the medium and favors the crystal growth, leading to larger needles. This effect seems to be very important in the CTAR system, the autoclave volume being smaller than that in the classical SAS process. For a capillary diameter of 128 µm, all the parameters are nearly the same for runs 6 and 7 except temperature, and the average particle size does not change. This indicates that temperature has no effect in this field of variation. Comparing those two runs with run 8, in the same domain of temperature but with a higher molar ratio, larger particles are obtained. This evolution is hence the same for the other capillaries. These results are obtained with the same initial griseofulvin mass concentration (10%) and the same CO2 flow rate (600 g · h-1). It is hence possible to conclude that this evolution is due to the increase of the organic solution flow rate, leading to a more important solvent content in the fluid phase which favors the crystal growth resulting in a higher average needle size. Concerning the capillary internal diameter, a size decrease leads to a global particle size decrease (sizes between 30 and 51 µm for a diameter of 500 µm and sizes between 26 and 34 µm for a diameter of 128 µm). This is due to the fact that a smaller diameter favors the organic solution dispersion (par-

ticularly by increasing the injection speed for the same flow rate) and therefore the formation of smaller particles. Eventually, the decrease of initial concentration of griseofulvin in the organic solvent gives smaller particles, as it can be shown with the run that leads to the smallest particle size (25 µm) for the smallest initial concentration (2 wt %). Concerning the influence of these operating parameters, it is possible to conclude that their influence is qualitatively similar to that of the classical SAS process, what is not surprising since the crystallization process principle is the same. However, some quantitative differences could be observed, and it could be interesting to make direct comparison between those two processes. Results Obtained for the Micronization of LPLA Employing the IT System. A quick overview of some results for the LPLA micronization using SCO2 as antisolvent has been conducted in order to formulate a critical comparison of our results. The major results are provided in Table 2. It is important to notice that LPLA has been micronized in very different operating conditions, in particular with capillary (or nozzle) diameters between 75 and 700 µm and using different antisolvent processes. When the micronization is successful, spheres are obtained. Some authors16,17,19 point out the typical development of fibers and films for initial mass concentrations higher than 3 wt %. Concerning the average particle size, the results are rather homogeneous with sizes of a few micrometers (particles obtained with the SEDS process are the only ones with sizes up to 25 µm). The results obtained in this work are presented in Table 4. For the IT system, the “global” molar ratio is defined as the ratio between the organic solution flow rate and the addition of the two CO2 flow rates (the one coming from the impinging jet and the global one). For the IT system, this parameter is not the most interesting one. It has been given in order to be exhaustive with respect to the experimental conditions tested. It is also important to control this parameter in order to have a sufficiently low organic solvent concentration in the medium and to avoid the redissolution of the solid. However, due to the specificity of the impinging jet technol-

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Table 4. Experimental Results for the Micronization of LPLA Using the IT Systema run

capillaries internal diameter (µm)b

injection speed (m · s-1)b

“global” organic solvent/CO2 molar ratio (%)

“local” organic solvent/CO2 molar ratio (%)

LPLA concentration (wt %)

1 2 3 4 5 6 7

500/128 500/128 500/128 500/128 500/128 500/500 500/500

0.42/0.99 0.42/1.97 0.85/1.97 -/1.97 0.85/1.31 0.13/0.13 0.09/0.09

4 7.5 6 10 4 6 4

15 30 15

1 1 1 1 1 3 3

a

10 100 100

size (µm) 1.44 2.08 2.30 film 2.14 1.72 2.07

( 0.82 ( 1.40 ( 1.07 ( 1.08 ( 0.90 ( 0.85

Solvent methylene chloride; pressure 10 MPa; temperature 308 K. b First number supercritical CO2; second number organic solution.

Figure 3. LPLA SEM picture (run 1; capillaries internal diameter 500 and 128 µm; LPLA concentration 1 wt %).

ogy, the important factor for interpretating the results is the value of this ratio between the two capillaries, in the impinging zone. This ratio, called “local” molar ratio, is calculated from the injection speeds of the organic solvent and CO2 using relation 4: local molar ratio )

dSuSFS /MS dCO2uCO2FCO2 /MCO2

(4)

where d stands for the capillary diameter (m), u, the injection speed (m · s-1), F, the density (kg · m-3), M, the molar mass (kg · mol-1), and subscript S, for organic solvent. The density of methylene chloride at 308 K is 1320 kg · m-3, and the density of supercritical CO2 at 10 MPa and 308 K is 650 kg · m-3 (these values come from the NIST database). For experiments 1-3 and 5, the capillary diameters are different for the two flows. In that case, the local molar ratio change is only due to speed change. For experiments 6 and 7, as the capillaries are the same and due to the values of density and mass molar of the compounds considered, this ratio is equal to 1. The results will be hence interpreted considering mainly the evolution of the injection speed. The main parameters studied in this case are the capillary size and the injection speeds. For all experiments, spheres are obtained, as it can be seen in Figure 3. The particle size is also very close to the sizes obtained for other studies, between 1 and 2 µm, confirming that the type of antisolvent process has a rather small influence on particle size in the case of LPLA micronization. However, it can be noticed that the IT system gives some of the smallest particle size among the different processes, shown in Table 2 with sizes up to 10 µm, and even 25 µm in one case. That means that the IT system is able to process the smallest particle size in comparison with other supercritical antisolvent processes. A similar explanation stands

Figure 4. Particle size distribution for runs 1-3 and 5 conducted with the IT process and two capillaries with different sizes (128 and 500 µm).

for the CTAR process. Indeed, in this system, a high mixing intensity is obtained between the two jets, leading to an important nucleation frequency and a global reduction of particle size. Run 4 has been conducted without CO2 injection, leading to the formation of a film, which is a typical drawback for LPLA recrystallization. In this study, it is interesting to see the influence of the speed injection of the two flows and the capillary sizes. The objective is to have a first optimization on these hydrodynamic parameters. The first runs (1-3 and 5) have been conducted with two capillary sizes, with CO2 being the biggest one, and two different injection speeds. Runs 1 and 2 have been conducted with the same CO2 injection speed and with a ratio 2 on the organic solution injection speeds. This speed increase leads to an increase of average particle size. In run 3, CO2 speed is also multiplied by 2, leading to another increase of the particle size. In run 5, the speed of the organic solution is decreased, leading to an intermediate value for the particle size. It must be noticed that the sizes obtained are not very far from each other (from 1.4 to 2.1 µm). In order to have more accurate statistical informations, the PSD of these different runs is given in Figure 4. It can be noted that this PSD is wider for runs 2 and 5 in comparison with runs 1 and 3. These different results indicate that the values of operating parameters tested do not allow a good control of the particle size. In particular, an increase of injection speed leads to an increase of particle size, which is not expected. It seems that the injection speeds are too high. Then, dispersion and mixing are unable to be controlled. That does not allow for good control of the crystallization process. Eventually, the use of two different sizes of capillaries is not pertinent. In order to overcome these drawbacks, some experiments have been conducted with the same capillary size (500 µm) and the injection speed (runs 6 and 7 in Table 4). In that case, an increase of the injection speed leads to a decrease of the average particle size from 2.1 to 1.7 µm. Besides, the PSDs


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that with the CTAR), even if the smallest sizes are not reached (see Table 2). For griseofulvin recrystallization, and in terms of particle size, these systems are intermediate between SAS classical processes and the more complex and more energy consuming ones. However, if a comparison is made on the basis of particle size/initial concentration in the organic solvent, it can be seen that these introduction devices are of great interest. Indeed, it is possible to process rather small particles with high initial concentration. For instance Table 2 shows that the SFED process gives small particles (less than 1 µm) but a very low initial concentration (0.8 wt %). In the case of the CTAR, it could be interesting working at higher flow rates in order to see if this could lead to a decrease of the particle size. This would need high pressure pumps different than the ones used in this work. Figure 5. Particle size distribution for runs 6 and 7 conducted with the IT process and the same capillary size (500 µm). Table 5. Comparison between IT and CTAR Performance CTAR

IT

LPLA

solute concentration solvent/CO2 ratio particle size ref

P ) 8-12 MPa T ) 308 K 1-6% 3.5-9 1-2 µm Boutin et al.8

solute concentration solvent/CO2 ratio particle size ref

P ) 10 MPa T ) 308-323 K 2-10% 1.5-10 25-50 µm this work

P ) 10 MPa T ) 308-313 K 1-3% 1-2 µm this work

griseofulvin P ) 10 MPa T ) 313 K 2.5-12% 25-50 µm Calvignac and Boutin9

presented in Figure 5 are more narrow. These results indicate that in the case of the IT system, it is preferable to use the same capillary size and rather small injection speeds. This allows good dispersion and mixing conditions control and, hence, good control of the crystallization process. Comparison of the Performance of the Two Injection Devices: CTAR and IT Systems. Table 5 sums up the different results obtained in this work and in previous works for the crystallization of two compounds (LPLA and griseofulvin) using two introduction devices: the CTAR and the IT systems. In this part, a comparison is done between those two systems and with other supercritical antisolvent devices. Concerning LPLA micronization, the particle sizes are very close for the two introduction devices. This information is not surprising as these results are the same with many introduction devices (see Table 2). However, the particle sizes are among the smallest in comparison with other processes. The main difference is the maximum initial concentration of LPLA in the organic solvent that leads to spheres and not to films or fibbers. This value is 3 wt % for the IT system and 6 wt % for the CTAR, which is much higher than with other systems (see Table 2). This point is interesting since it allows an intensification of the process, in terms of global yield and CO2 and organic solvent consumption. Concerning the micronization of griseofulvin, the CTAR allows decreasing significantly the particle size, in comparison with classical antisolvent process, but not with more sophisticated processes (see Tables 1 and 2). This decrease is much more important with the IT system (roughly twice smaller than

Conclusion To conclude, these two introduction devices give interesting results for particle generation. More precisely, they allow the reduction of the average particle size and processing high concentrated organic solution. This is due to an intensification of the mixing between the organic solvent jet and the surrounding SCO2. This fact has an important effect on the supersaturation profile and nucleation frequency. This type of explanation has also been proposed by Mawon et al.29 for a different configuration. For some aspects, the IT system gives better results than the CTAR. However, this system is more complex to process, in particular for maintaining constant impinging conditions during the experiment. Besides, the IT system is more energy consuming as it needs one more pump than the CTAR. The results obtained here must encourage testing these processes on other molecules in order to compare their performance with more classical introduction devices. Eventually, these introduction devices, in particular the CTAR, present some advantages for process intensification.4 It is possible to multiply the number of tubes in order to increase the powder production keeping the same experimental conditions in each tube. Literature Cited (1) Charbit, G.; Badens, E.; Boutin, O. Methods of Particle production. Drugs DeliVery in Supercritical Technology; Marcel Dekker: New York, 2004. (2) Moneghini, M.; Kikic, I.; Voinovich, D.; Perissutti, B.; Alessi, P.; Cortesi, A.; Princivalle, F.; Solinas, D. Study of the solid state of carbamazepine after processing with gas anti-solvent technique. Eur. J. Pharm. Biopharm. 2003, 26, 281. (3) Yeo, S. D.; Kim, M. S.; Lee, J. C. Recrystallization of sulfathiazole and chlorpropamide using the supercritical fluid antisolvent process. J. Supercrit. Fluids 2003, 25, 143. (4) Tenorio, A.; Gordillo, M. D.; Pereyra, C.; De la Ossa, E. J. M. Controlled submicro particle formation of ampicillin by supercritical antisolvent precipitation. J. Supercrit. Fluids 2007, 40, 308. (5) Reverchon, E. Supercritical antisolvent precipitation of micro- and nano-particles. J. Supercrit. Fluids 1999, 15, 1. (6) 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, 239. (7) Kim, M. S.; Lee, S.; Park, J. S.; Woo, J. S.; Hwang, S. J. Micronization of cilostazol using supercritical antisolvent (SAS) process: Effect of process parameters. Powder Technol. 2007, 177, 64. (8) Boutin, O.; Maruejouls, C.; Charbit, G. A new system for particle formation using the principle of the SAS process: The Concentric Tube antisolvent Reactor. J. Supercrit. Fluids 2007, 40, 443. (9) Calvignac, B.; Boutin, O. The impinging jets technology: a contacting device using a SAS process type. Powder Technol. 2009, 191, 200–205.

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(21) Ghaderi, R.; Artursson, P.; Carlfors, J. Preparation of biodegradable microparticles using solution enhanced dispersion by supercritical fluids (SEDS). Pharm. Res. 1999, 16, 676. (22) Ghaderi, R.; Artursson, P.; Carlfors, J. A new method for preparing biodegradable microparticles and entrapment of hydrocortisone in DL - PLG microparticles using supercritical fluids. Eur. J. Pharm. Sci. 2000, 10, 1. (23) Rantakyla¨, M.; Ja¨ntti, M.; Aaltonen, O.; Hurme, M. The effect of initial drop size on particle size in the supercritical antisolvent precipitation (SAS) technique. J. Supercrit. Fluids 2002, 24, 251. (24) Jarmer, D. J.; Lengsfeld, C. S.; Randoph, 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, 242. (25) Obrzut, D. L.; Bell, P. W.; Roberts, C. B.; Duke, S. R. Effect of process conditions on the spray characteristics of a PLA + methylene chloride solution in the supercritical antisolvent precipitation process. J. Supercrit. Fluids 2007, 42, 299. (26) Tsivintzelis, I.; Missopolinou, D.; Kalogiannis, K.; Panayiotou, C. Phase composition and saturated densities for the binary systems of carbon dioxide with ethanol and dichloromethane. Fluid Phase Equilib. 2004, 224, 89. (27) Chiehming, C.; Kou-Lung, C.; Chang-Yih, D. A new apparatus for the determination P-x-y diagrams and Henry’s constants in high pressure alcohols with critical carbon dioxide. J. Supercrit. Fluids 1998, 12, 223. (28) FDA. International Conference on Harmonisation, ICH Guidance on Impurities: Residual solvents. Federal Register 1997, 62, 67377. (29) Mawson, S.; Kanakia, S.; Johnston, K. P. Coaxial Nozzle for Control of Particle Morphology in Precipitation with a Compressed Fluid Antisolvent. J. Appl. Polym. Sci. 1997, 64, 2105.

ReceiVed for reView November 20, 2008 ReVised manuscript receiVed February 8, 2009 Accepted April 27, 2009 IE8017803

Powder Micronization Using a CO2 Supercritical

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