4718
Ind. Eng. Chem. Res. 1996, 35, 4718-4726
Particle Production of Steroid Drugs Using Supercritical Fluid Processing P. Alessi, A. Cortesi, and I. Kikic* Dipartimento di Ingegneria Chimica, dell’Ambiente e delle Materie Prime, Universita` di Trieste, 34127 Trieste, Italy
N. R. Foster and S. J. Macnaughton School of Chemical Engineering and Industrial Chemistry, University of New South Wales, Sydney, NSW, Australia 2052
I. Colombo Vectorpharma Intl. S.p.A., Via del Follatoio 12, 34148 Trieste, Italy
The manufacture of fine particles of two steroid drugssprogesterone and medroxyprogesterone acetateshas been investigated through the rapid expansion of supercritical solutions (RESS). The motivation was the production of particles with improved characteristics for use in the pharmaceutical industry. Solubility data for each drug in supercritical CO2 were measured prior to performing the RESS experiments as these data are essential for accurate experimental design. The solubility data were measured using a dynamic apparatus at pressures between 100 and 240 bar and at 313.1 and 333.1 K. Particles were manufactured by expanding a solution of supercritical CO2 saturated with drug through a micronozzle to pressures of 50 bar or less. A sufficient amount of particles was manufactured to allow particle characterization tests to be completed. Particle size, particle size distribution, and specific surface area were used as assessment measures to compare the product samples obtained in different experimental conditions. The RESS technique produced particles that were significantly smaller than existing samples manufactured using jet-milling. Introduction Particle size is a key factor for the performance in the use of different organic and inorganic materials. The first observation on the possibility of obtaining ultrafine powder through supercritical fluid processing and in particular from a decompression of the fluid is dated to Hannay (Hannay and Hogarth, 1879), but only Krukonis (Krukonis, 1984) revived the interest, demonstrating its potentiality for processing a variety of difficult to comminute solids. The great advantage of using supercritical fluids is in the possibility of producing solid phases with unique morphology at mild operating conditions. There exist actually different ways for particle size formation using supercritical fluids: the antisolvent process (SAS), the particles from gas saturated solutions (PGSS), and finally the rapid expansion from supercritical solutions (RESS). In the case of SAS (Gallagher et al., 1989; Chang and Randolph, 1990; Dixon and Johnston, 1991; Yeo et al., 1993a,b; Bleich et al., 1993), the material from which particles will be formed is initially dissolved in a common solvent (depending on the nature of the solute, the solvent will be an inorganic or organic compound). The supercritical solvent (commonly carbon dioxide) is added to the solution, and, in general, it exhibits more favorable interactions with the solvent than with the solute. As a consequence, the original solvent is preferentially soluble in the supercritical phase and a large variation (decrease) of density is obtained. Both effects act in the right direction for the reduction of the solubility of the solute which will precipitate. The morphology and the particle sizes of the solute are S0888-5885(96)00202-3 CCC: $12.00
mainly connected to the volumetric expansion of the solution and to the rate of addition of the supercritical fluid. PGSS and RESS are used in the absence of other solvents: the systems to be processed are mainly binary systems (the solute and the supercritical fluid), which, at a given temperature and pressure, are instable and will originate a two-phase system. At high temperature (higher than the melting point of the solute) these two phases are liquids: one is richer of the supercritical fluid (normally carbon dioxide) with a low content of the solute, and the second one is constituted by the liquid organic solute in which the supercritical fluid is dissolved. In the PGSS process (Weidner et al., 1994) the solute-rich phase is then depressurized through a nozzle. In the RESS process the equilibrium between solute and supercritical fluid is reached at temperatures well below the melting point of the solute so that the two phases are the solid phase (almost pure solute) and the supercritical phase (in which the solute is partially dissolved). The dilute supercritical phase is then depressurized in order to precipitate solid particles. Both in the PGSS and in the RESS fine particles are obtained through the precipitation after a rapid expansion as a consequence of the drastic reduction of solubility. PGSS presents the advantage of processing a concentrated solution of the compound of interest: as a consequence, high productivity is obtained. On the contrary, RESS, with respect to PGSS, presents the advantage of a process at lower temperature: the thermal degradation of the organic solute is minimized. Even if the three processes have different fields of application, they can be considered as complementary. A rough estimate for the choice of the process can be given on the basis of solubility considerations: if the © 1996 American Chemical Society
Ind. Eng. Chem. Res., Vol. 35, No. 12, 1996 4719
Figure 1. Solubility apparatus.
solubility of the material of interest in supercritical fluid is higher than some milligrams per gram of solvents, the RESS process can be used; if the solubility is lower, the SAS process is preferred. Finally PGSS can be used in the case of low melting point and relatively no thermolable materials. In conclusion, the use of these techniques allows the processing of a wide range of materials (and in this way it is possible to obtain solid materials with desired morphologies). In this work we have investigated the possibility of applying the RESS technique for the micronization of some steroid drugssprogesterone and medroxyprogesterone acetate. The progesterone is an intermediate product extremely important for the biosynthesis of other steroid hormones such as testosterone and of estrogen. It is essential for pregnancy and its correct evolution, and it shows positive effects on protein transport and for the electrolytic balance. Normally, it can be assumed orally or as an injectable drug for both the minimization or the maximization of biological effects of endogenous hormones, for increasing a insufficient production, for the correction of unbalanced hormones, and as a contraceptive. For this last action the synthetic derivatives as the medroxyprogesterone acetate or the megestrol acetate (Shacter et al., 1989; Tchekmedyian et al., 1987) are more effective due to the fact that, contrary to progesterone, they are not disactivated so that they have a more prolonged action and they can constitute a reservoir. The effectiveness of all these drugs is extremely sensitive to their size and total surface, with their dissolution rate being dependent from these factors. For these reasons in the present paper the possibility of using supercritical fluids for increasing these properties is investigated. The paper is organized in order to present in the first part the solubility investigation and in the following the RESS results obtained.
Experimental Techniques and Chemicals Used Materials. Progesterone and medroxyprogesterone acetate were obtained from Upjohn Co., Kalamazoo, MI, and from Farmitalia C. Erba, Milano, Italy, with a purity of 99.5%. Carbon dioxide was obtained from SIAD at a purity of 99.98%. Solubility Measurements. The technique used for the determination of the solubility is a dynamic one. The apparatus is similar to that described in a previous work (Macnaughton et al., 1995), and it is reported in Figure 1. Liquid carbon dioxide (food grade, 99.8% minimum purity) was fed through a 2 µm filter to a pump (Constametric 3000 P/F-LDC). The CO2 was compressed and pumped into a preheating coil contained in a temperature-controlled air bath. Thermal equilibrium was achieved in the preheating coil, and the fluid then passed into an equilibrium cell packed with solute and plugged at each end with glass wool to eliminate entrainment. The solute-laden CO2 leaving the cells was directed through a 0.5 µm filter to prevent physical entrainment. The fluid was then flashed to atmospheric pressure through a regulating valve, resulting in the precipitation of solute within both the valve and a 0.5 µm filter attached immediately downstream of the valve. The gas released through the regulating valve was passed through a water saturator and a wet test meter for volume determination. During each experiment the system pressure was maintained to within (0.2% of the desired value by adjusting the regulating valve and the pump flow rate. The system temperature was controlled to within (0.1 K using an immersion circulator (Haake N3). The determination of solubility was based on the mass of solute trapped in a valve and filter and the corresponding volume of CO2. The gas volume was measured with a precision of 0.01 L using a wet test meter (SIM Brunt) that was calibrated to an accuracy of (0.4%. The mass of solute was determined to (0.2 mg using a Mettler H31 balance. The typical mass of solute collected in
4720 Ind. Eng. Chem. Res., Vol. 35, No. 12, 1996
Figure 2. Micronization apparatus.
each experiment was greater than 100 mg, giving a potential error due to weighing of (0.2%. The system temperature was measured using a RTD platinum probe accurate to (0.1 K, and the system pressure was measured using a Druck pressure transducer (DPI 260) accurate to (0.1%. The reliability and efficiency of the experimental apparatus and of the experimental technique were already checked by measuring the solubility of salicyclic acid in supercritical CO2 (Macnaughton et al., 1995). RESS Measurements. The main features of the process are outlined in Figure 2 where the unit for RESS is represented. The experimental apparatus was constituted by two parts: the solubilization unit and the expansion or crystallization part. The solvent (liquid carbon dioxide) from the reservoir flowed through a filter F1 and then in a cooler, where the temperature was maintained at 273 K in order to prevent the formation of bubbles in the pump. By means of the pump (Constametric 3000 P/F-LDC), the desired pressure was reached and the carbon dioxide flowed in the extraction section through a capillary tube which was maintained at the same temperature as the extractors (valve V2 open and valve V4 closed). Different concentrations of the solute can be reached by partially opening valve V4 so that part of the supercritical solvent bypasses the extraction unit. In this case the control of the concentration is made through the flowmeter FM. The supercritical solution through a thermostated tube was connected to the crystallizer. Before the nozzle there was also a preheating part where the temperature was controlled (Watlow Series 965). The nozzle represented the most important part of the whole apparatus. It was constituted by a disk in stainless steel in which holes of different diameters have been obtained with a laser. Different length/diameter (L/D) ratios were used, ranging from 6 to 20. The crystallizer of cylindrical shape was thermostated in order to maintain the postexpansion temperature constant. The temperature was read with a Pt thermocouple (Delta Ohm HD9214). The pressure in the crystallizer was measured by a pressure transducer (DS EUROPE AN341) and was maintained at the desired value through the valve V7. The flowrate was measured at the outlet after a filter
F2. In order to avoid solvent condensation and to control the pressure, nitrogen or carbon dioxide was injected in the expansion chamber. Particle Characterization. The morphology of the particles obtained were studied through optical microscopy; average and particle size distribution of the samples were derived from the Mayer and Stowe model (Mayer and Stowe, 1965) through mercury porosimetry (C. Erba Model 2000). According to this model a cumulative percentage volume oversize distribution can be derived; from this property via differentiation a differential volume distribution can be estimated (Lowell and Shields, 1984). Specific surface areas were calculated with the Rootare and Preazlow method (Rootare and Preazlow, 1967). In order to assure that no modifications were introduced after the expansion, DSC measurements (DSC 7, Perkin-Elmer) were performed on the starting material and on the material processed with supercritical carbon dioxide. Solubility Investigation Background. For establishing the best technique for the micronization of these drugs using supercritical fluids, the solubility should be known. The effect of different physicochemical parameters can be better understood if solubility in the supercritical fluid is known as a function of temperature and pressure. A literature search was performed in order to check if solubility data were available for the drugs of interest. In Table 1 solubility data for steroid drugs are summarized. No data exist for medroxyprogesterone acetate, while for progesterone data were measured by Kosal (Kosal et al., 1992). Experimental data for the two drugs were measured with the apparatus described in the Experimental Section. Results and Discussion. Results obtained are reported in Table 2. Each data point is the result of at least four repeated measurements: in some cases these measurements were also repeated until a satisfactory reproducibility was obtained. The maximum deviation among the measurements was 3.5%, giving a good indication of the
Ind. Eng. Chem. Res., Vol. 35, No. 12, 1996 4721 Table 1. Solubility of Steroid Drugs in Supercritical Fluids (Literature) steroid cholesterol
ref
S.F.
Stahl et al. (1978) Chrastil (1982) Wong and Johnston (1986) Wong and Johnson (1986) Wong and Johnston (1986) Wong and Johnston (1986) Kosal et al. (1992) Kosal et al. (1992) Yun et al. (1991) Yeh et al. (1991) Foster et al. (1993)
CO2 CO2 CO2 CO2 CO2 CO2 CO2 CO2 CO2 CO2 C2H6 C2H6 CO2 CO2 C2H6 C2H6 C2H6 C2H6 C2H6 C2H6 CO2 CO2 CO2 CO2 CO2 CO2 CO2 CO2 CO2 CO2 CO2
Ekart et al. (1993)
Singh et al. (1993)
ergosterol
Stahl and Glatz (1984) Wong and Johnston (1986) Kosal et al. (1992) Stahl and Glatz (1984) Wong and Johnston (1986)
progesterone sitosterol stigmasterol
testosterone
Kosal et al. (1992)
cosolvent
acetone ethanol methanol N2O hexane acetone hexane acetone ethanol isopropanol trifluoroethanol acetone propane ethane
N2O acetone ethanol methanol
T (K)
P (bar)
313 313 308-333 308 308 308 328-333 333 313-333 313 318-338 318-338 318-338 318-338 323 323 323 323 313-338 313-338 313-338 313 308 308-328 308-333 313 308-333 308 308 308 308-328
85 100-200 101-279 100-277 101-354 105-278 100-272 107-248 100-250 100-175 70-190 70-190 90-220 100-220 100-200 80-200 100-200 80-200 80-220 80-220 80-220 80-200 251-277 100-240 92-240 80-200 90-277 100-304 101-355 101-304 85-240
Table 2. Solubility Data for Progesterone and Medroxyprogesterone Acetate temperature (K)
pressure (bar)
313
90 115 145 175 205 240 115 145 175 205 240
333
313
333
density (g cm-3)
solubility (mole fraction × 104)
Progesterone 0.494 0.705 0.774 0.815 0.846 0.874 0.398 0.586 0.678 0.733 0.777
0.18 1.64 3.15 4.66 5.99 7.20 0.09 1.11 2.78 4.86 7.37
Medroxyprogesterone Acetate 110 0.686 150 0.782 180 0.821 220 0.859 150 0.606 180 0.689 200 0.725 220 0.754
0.29 0.767 1.01 1.63 0.331 0.740 1.10 1.32
results’ accuracy because the individual equipment errors which contribute to the overall error (i.e., pressure, temperature, mass, and volume) are all below this level. In Table 2 also the density of the supercritical carbon dioxide (Angus et al., 1976) is reported at the experimental conditions. Data obtained for progesterone were compared with those reported in the literature (Kosal et al., 1992); the solubilities measured in this work are, at all pressures, higher. Similar discrepancies are observed also between data reported by Kosal for cholesterol and those measured by other authors (Yun et al., 1991; Yeh et al., 1991; Wong and Johnston, 1986). The possible explanation is the analytical procedure employed by Kosal for determining the concentration of the drugs in the supercritical phase; they derivatized the drugs, transforming them into an ester. From this procedure errors
Figure 3. Effect of density on the solubility of progesterone (parameters of the correlations a313 ) 6.50, b313 ) -51.30, AARD313 ) 3.21%; a333 ) 6.55, b333 ) -50.82, AARD333 ) 2.15%).
higher than those obtained with a gravimetrical determination could arise. It is evident from the experimental data reported that for progesterone the crossover region is in the range of pressures between 205 and 240 bar whereas for medroxyprogesterone acetate the crossover region occurs at a pressure higher than those investigated. The effect of density on the solubility is evidenced in Figures 3 and 4 for progesterone and medroxyprogesterone acetate, respectively. The line reported in the figure is the result of the empirical correlation between the logarithm of the solubility and the logarithm of the supercritical fluid density (Kumar and Johnston, 1987) following the equation
ln y ) a ln F + b
(1)
The numerical values of the constants a and b for the two steroids studied together with the AARD obtained
4722 Ind. Eng. Chem. Res., Vol. 35, No. 12, 1996
Figure 4. Effect of density on the solubility of medroxyprogesterone acetate (parameters of the correlations a313 ) 7.49, b313 ) -59.39, AARD313 ) 4.55%; a333 ) 6.46, b333 ) -51.68, AARD333 ) 2.21%). Table 3. Results of the Empirical Correlation temp (K) 313 333 313 333
slope
intercept
AARD (%)
Progesterone 6.50 -51.30 6.55 -50.82
3.21 2.15
Medroxyprogesterone Acetate 7.49 -59.39 6.46 -51.68
4.55 2.21
are reported in the same figures: as can be seen from the AARD the data are satisfactorily correlated with this empirical relation (Table 3). The equation of state approach was also used for the correlation of the solubility. The solubility of a solid solute at equilibrium conditions in a fluid at high pressures can be calculated using the expression (Prausnitz et al., 1986)
[
v1 Psub 1 (P - Psub y1 ) exp 1 ) Pφ ˆ1 RT
]
(2)
where subscripts 1 and 2 refer respectively to the solute and to the solvent; Psub is the sublimation pressure, v1 1 is the molar volume of the solid, and φˆ 1, the fugacity coefficient in the fluid phase, takes explicitly into account the nonideality of the fluid phase. The fugacity coefficient can be calculated with an equation of state; the Peng-Robinson equation was used with the classical mixing rules. As reported elsewhere (Kikic et al., 1995), the main problem for correlating solubility data of pharmaceutical compounds, or more generally high molecular weight and complex molecules, in supercritical fluids is the knowledge of pure component properties of the interested compound. Different group contribution methods (Reid et al., 1988) can be used for the evaluation of critical properties, but sublimation pressures are difficult to evaluate and also their measurement is questionable (often beyond the limits of experimental methods available). Consequently, the best approach is to consider the sublimation pressure as a fitting variable together with the binary interaction parameter. In Figure 5 a comparison between experimental data and calculated ones is reported for progesterone: the average deviations are 5.2%. Similar results were obtained for medroxyprogesterone acetate: the parameters used are reported in Table 4 together with those of progesterone.
Figure 5. Correlation with PR equation of state for progesterone.
RESS Investigation Background. In the case of pharmaceutical products the particle size is quite important since it can limit the bioavailability of poorly soluble active principles. As an example we can refer to the data obtained for the griseofulvin: Atkinson (Atkinson et al., 1962) has studied the concentration of the drug in the blood, taken from healthy volunteers at given intervals of time after dosing, as a function of its specific area (opposite of the particle size). The quantity absorbed for a particle size of 2.7 µm is 2 times that obtained with a particle size of 10 µm. These results have also been confirmed by different authors with other pharmaceutical products, like gliburide (Pedersen, 1977). Also in the controlled drug release the size of the active principle is very important in order to facilitate the diffusion of the pharmaceutical product through the polymer in which it is dispersed and the dissolution in the blood (Chang et al., 1987). Different authors have studied the possibility of using RESS technique for the reduction of particle size of pharmaceutical products; in Table 5 these studies are summarized. For a given drug the supercritical fluid used, the saturation temperature and pressure, and the preexpansion temperature are reported. Results and Discussion. As evidenced recently by various authors (Mohamed et al., 1989a,b; Reverchon et al., 1993; Tom et al., 1994), different factors can influence the characteristics and the structure of the micronized drugs: concentration of supercritical solution, pre- and postexpansion temperatures and pressures, and obviously the nozzle geometry and diameter. In this investigation we have not investigated the effect of preexpansion temperature and pressure since these were maintained constant for all the runs. It is necessary, however, to put in evidence that due to the solubility behavior observed for the progesterone the saturation temperature and pressure investigated were at conditions below the crossover region. As a consequence, immediately prior to the nozzle (preexpansion conditions) it was always necessary to reduce the temperature with respect to that of saturation in order to avoid the precipitation of the drugs before the expansion. This is exactly the contrary of what is normally done by many investigators (Mohamed et al., 1989a,b; Reverchon et al., 1993) operating over the crossover. Due to the similar properties of the two drugs, the influence of different RESS operating parameters was investigated for the progesterone only and the results
Ind. Eng. Chem. Res., Vol. 35, No. 12, 1996 4723
Figure 6. Particle size distribution obtained with nozzle diameters of 30 and 100 µm.
subsequently checked on medroxyprogesterone acetate. The parameters investigated in the present study were the saturation pressure (130-250 bar), the preexpansion and postexpansion temperatures (between 30-42 and 40-60 °C, respectively), postexpansion pressure (150 bar), and obviously the nozzle diameter (30-100 µm). Nozzle Diameter. The influence of this parameter can be evaluated from the results obtained with a nozzle diameter of 100 and 30 µm: the average diameters of the particles were 7.5 and 4.1 µm, respectively. From the difference in particle size a large difference for the cumulative surface area for the samples collected also follows. In Figures 6 and 7 particle size distribution and cumulative area distribution obtained are reported. Saturation Pressure. Following the literature a decrease in saturation pressure (or in concentration) induces a marked increase of particle sizes due to lower supersaturation and to the decrease of nucleation rate. For the evaluation of this parameter different runs with saturation pressures of 130 and 150 bar, respectively, were performed; the solubility increases from 4.55 × 10-5 to 1.35 × 10-4, and as a consequence, the average size decreases also from 7.5 to 6.0 µm (Figures 8 and 9). Postexpansion Pressure. This parameter has a marked influence on the size and the form of the
Figure 7. Cumulative surface area distribution obtained using nozzle diameters of 30 and 100 µm.
Figure 8. Particles obtained by RESS: saturation pressure, 130 bar; saturation temperature, 60 °C; postexpansion pressure, 1 bar; postexpansion temperature, 40 °C.
particles obtained. Reducing the postexpansion pressure from 50 to 20 bar and 1 bar, the average particle size decreases from 9.1 to 7.5 µm, always with a similar
Table 4. Parameters Obtained by Fitting Experimental Data with Peng-Robinson Equation of Statea compound
Tc (K)
Tb (K)
Pc (bar)
ω
Vm
Kij
Psub (333 K)
progesterone medroxyprogesterone acetate
932.3 987.43
684.7 708.5
19.15 14.22
0.52 0.96
281.7 252.4
0.00 0.03
4.26 × 10-9 4.4 × 10-12
a For progesterone, T , T , and V are taken from Kosal et al. (1992) and P was calculated with the Joback method (Reid et al., 1988); c b m c for medroxyprogesterone acetate, Tc and Tb were calculated with Fedors and Klincewitz methods, respectively, Pc with the Joback method (Reid et al., 1988), and Vm with the Immirzi-Perini method (Immirzi and Perini, 1977).
Table 5. RESS Experiences for Pharmaceutical Products material
supercritical fluid
ref
Psat (bar)
Tsat (K)
β-estradiol soia lecitine phenacetine mevinolin L-630.028 (steroid derivative) lovastatin β-carotene benzoic acid benzoic acid L-leucina stigmasterol salicylic acid lovastatin-L-PLA griseofulvin nifedipin carotenoids
CO2 CO2 CO2-CHF3 CO2 CO2 CO2 ethylene ethylene + toluene CO2 CO2 CO2 CO2 CO2 CO2 CHF3 CO2 CO2, ethane, ethylene, ...
Krukonis (1984) Krukonis (1984) Loth and Hemgesberg (1986) Larson and Kin (1986) Larson and King (1986) Mohamed et al. (1989a,b) Chang and Randolph (1989) Tavana and Randolph (1989) Berends et al. (1993) Furuta et al. (1992) Ohgaki et al. (1990) Reverchon et al. (1995) Tom et al. (1992) Reverchon et al. (1995) Gerard and Quinin (1987) Best et al. (1979)
345 345 600-599
328 328 333-353
300 200-283 160-280 103 150
343 308-328 308-338
200-250 180-220 600 80-400
328 333 343 298-323
306
Tpreexp (K)
403 423-573 373-423 348-353 333-423
4724 Ind. Eng. Chem. Res., Vol. 35, No. 12, 1996
Figure 11. Comparison between particle size distribution of progesterone micronized by jet mill and by RESS. Figure 9. Particles obtained by RESS: saturation pressure, 150 bar; saturation temperature, 60 °C; postexpansion pressure, 1 bar; postexpansion temperature, 40 °C.
Figure 12. Different distributions for the particles obtained by jet mill.
Figure 10. Particles obtained by RESS: saturation pressure, 150 bar; saturation temperature, 60 °C; postexpansion pressure, 50 bar; postexpansion temperature, 40 °C.
distribution of the sizes. The more interesting aspect, however, is represented by the morphology of the particles of progesterone obtained: the particles at 50 bar have a dendrite structure (Figure 10), whereas at 1 bar they have a prismatic structure (see Figure 9). The dendrite structure is formed from the growing and coagulation of the primary particles: as a consequence, they need a surrounding characterized by moderate conditions such as that obtained through limited depressurization conditions. In these conditions the suprasaturation ratio is lower with respect to that obtainable with a large depressurization ratio, and the nucleation rate is lower: as a consequence, the particles can grow and become larger than those obtained at lower expansion pressures. Postexpansion Temperature. In all the experiments in which this effect was studied, an increase of particle sizes was observed by increasing the postexpansion temperature from 40 to 60 °C. This negative effect was better observed in the runs in which the postexpansion pressure was maintained at 1 bar. In these cases the average particle size slightly increases and also the total specific surface decreases from 1.18 to 1.08 m2/g. This effect can be explained with the fact
Figure 13. Comparison between cumulative specific area distribution of progesterone micronized by jet mill and by RESS.
that higher temperatures increase the growing of the particles. The reduction of particle sizes as a consequence of the decrease of postexpansion temperature suggests the possibility of separating the two processes of nucleation and growth. Whereas the postexpansion pressure seems without influence on the size distribution, the increase of the postexpansion temperature gives a more homogeneous distribution of the particle sizes. Comparison with Milling Techniques. Micronization of progesterone was successfully performed by RESS. The quality of the material produced is evidenced in Figures 11-13 where the materials obtained
Ind. Eng. Chem. Res., Vol. 35, No. 12, 1996 4725
Figure 14. Particles of progesterone micronized by RESS (saturation pressure, 150 bar; saturation temperature, 60 °C; preexpansion temperature, 8 °C; postexpansion pressure, 1 bar; postexpansion temperature, 40 °C; nozzle diameter, 30 µm) and by jet mill.
by RESS and that micronized by a classical technique (jet mills) are compared. In Figure 11 the particle size distributions are reported. The jet mills give particles with an average particle size of 7.5 µm, whereas with the RESS process particles of 4.5 µm are obtained. Also the distribution of particle sizes is different: a narrow distribution is obtained with RESS. With the jet mills process the global distribution is, in reality, the sum of different distributions (see Figure 12). In Figure 13 cumulative specific surface area distributions are reported: 2.08 m2/g is the value obtained for the RESS particles, whereas 1.45 m2/g is the value obtained with the jet mills technique. This means that the RESS technique allows an increase of more than 40% for the cumulative specific surface area. The differences between particles obtained with the two techniques are also evidenced in the pictures reported in parts a (RESS) and b (jet mill) of Figure 14. In Figure 15 results obtained for medroxyprogesterone acetate are evidenced: also in this case the materials micronized by RESS (Figure 15a) and by jet mill (Figure 15b) are reported. Moreover, DSC measurements show that also the two pharmaceutical products were not affected by the treatment with the supercritical fluid.
Figure 15. Particles of medroxyprogesterone acetate micronized by RESS (saturation pressure, 150 bar; saturation temperature, 60 °C; preexpansion temperature, 38 °C; postexpansion pressure, 1 bar; postexpansion temperature, 40 °C; nozzle diameter, 30 µm) and by jet mill.
Acknowledgment The authors acknowledge financial support from ARC Fellowship Supercritical Fluid Desorption of Solutes from Solid Matrices (Ref. No. F4934066) and ARC Collaborative Research Grant with BVR Pty Ltd. (Ref. No. C29380035) as well as CNR and MURST. Literature Cited Angus, S.; Armstrong, B.; de Reuck, K. M. IUPAC International Tables of the Fluid StatesCarbon Dioxide; Pergamon Press: New York, 1976. Atkinson, R. M.; Bedford, C.; Child, K. J.; Tomich, E. G. Effect of Particle Size on Blood Griseofulvin-Levels in Man. Nature 1962, 193, 588. Berends, E. M.; Bruinsma, O. S. L.; van Rosmalen, G. M. Nucleation and growth of fine Crystals from Supercritical Carbon Dioxide. J. Cryst. Growth 1993, 128, 50. Best, W.; Muller, F. J.; Schmieder, K.; Frank, R.; Paust, J. Germ. Pat. Appl. 29 42 267 (BASF AG), 1979 (as reported in Stahl, E.; Quirin, K.-W.; Gerard, D. Dense Gases for Extraction and Refining; Springer-Verlag: Berlin, 1987). Bleich, J.; Muller, B. W.; Wassmus, W. Aerosol Solvent Extraction System: A New Microparticle Production Technique. Int. J. Pharm. 1993, 97, 111. Chang, C. J.; Randolph, A. D. Precipitation of Microsize Organic Particles from Supercritical Fluids. AIChE J. 1989, 35, 1876. Chang, C. J.; Randolph, A. D. Solvent Expansion and Solute Solubility Predictions in Gas-Expanded Liquids. AIChE J. 1990, 36, 939.
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Received for review April 2, 1996 Revised manuscript received July 15, 1996 Accepted July 15, 1996X IE960202X X Abstract published in Advance ACS Abstracts, November 1, 1996.
