4794 Ind. Eng. Chem. Res. 2000, 39, 4794-4802 Micronization by Rapid Expansion of Supercritical Solutions to Enhance the Dissolution Rates of Poorly Water-Soluble Pharmaceuticals M. Charoenchaitrakool, F. Dehghani, and N. R. Foster* School of Chemical Engineering and Industrial Chemistry, The University of New South Wales, Sydney, Australia, 2052 H. K. Chan Faculty of Pharmacy, The University of Sydney, Sydney, Australia, 2006 The dissolution of a drug into the biological environment can be enhanced by reducing the particle size of the drug. In this study the rapid expansion of supercritical solutions (RESS) process was employed to micronize racemic ibuprofen, and the dissolution rate of the micronized product in a buffered solution was examined. The chiral nonsteroidal antiinflammatory, racemic ibuprofen, was used as a model drug because its dissolution rate is limited by its poor solubility in water. The phase behavior of the ibuprofen-CO2 binary system was investigated prior to the solubility measurements being undertaken. The solubility of racemic ibuprofen in supercritical CO2 was measured using a dynamic apparatus at pressures between 80 and 220 bar and temperatures of 35, 40, and 45 °C. The solubility data was modeled using the Peng-Robinson equation of state with van der Waals mixing rules. The ratio of R and S isomers in the extract was found to be the same as that in the original material. The solubility of pure optical isomers of ibuprofen, namely, (S)-ibuprofen and (R)-ibuprofen, were also determined at 35 °C within the pressure range of 80-200 bar. It was found that (S)-ibuprofen exhibited solubility in CO2 similar to (R)- ibuprofen, and the solubility of the pure isomers was at least 60% higher than that of the racemic ibuprofen at all pressures. The RESS experiments involved studying the effect of spraying distance, the pre-expansion pressure, and nozzle length on the particle size. The median particle size of ibuprofen precipitated by RESS was less than 2.5 µm. Although the particles obtained were aggregated, they were easily dispersed by ultrasonication in water. The pre-expansion pressure and nozzle length had no effect on the particle size and morphology within the range of operating conditions studied. An increase in spraying distance resulted in a slight decrease in particle size and degree of aggregation. The powder dissolution rate of racemic ibuprofen was enhanced as the particle size decreased. The degree of crystallinity of the processed ibuprofen was slightly decreased; as a result, the micronized product exhibited a higher disk intrinsic dissolution rate. The increase in dissolution rate of ibuprofen was hence due to both the reduction in particle size and the degree of crystallinity. Introduction zation of particles. In the RESS process, solutes are dissolved in a supercritical fluid, resulting in a solute- Many drugs exhibit poor solubility in water, and their laden supercritical phase. By reduction of the pressure absorptions in the gastrointestinal tract are limited by across an expansion device, fine particles with a narrow their dissolution rates. In the pharmaceutical industry, size distribution can be obtained. One advantage of micronization techniques are used to improve dissolu- micronization by the RESS process is the ability to tion rates of drugs into the biological environment. produce solvent-free product without the need for ad- Several conventional techniques have been utilized for ditional solvents or surfactants to induce precipitation. particle size reduction. These include mechanical com- Low critical temperature solvents such as CO2 (Tc ) minution (crushing, grinding, and milling), spray-dry- 31.1 °C) can be used for the precipitation of thermally ing, freeze-drying, and recrystallization of the solute labile materials without the risk of degradation. The particles from solutions using liquid antisolvents. The application of RESS can also be extended to the pro- disadvantages of using these conventional techniques cessing of shock and chemically sensitive substances, are thermal and chemical degradation of products, large for the formation of thin films and fibers, for microen- amounts of solvent use and associated disposal prob- capsulation, and for mixing of powders.2 lems, broad particle size distributions, and solvent Ibuprofen is a chiral nonsteroidal antiinflammatory 1 residues. drug (NSAID) of which the (S)-(+)-enantiomer exhibits A novel technique, the rapid expansion of supercritical higher antiinflammatory activity than the (R)-(-) enan- solutions (RESS), was recently developed for microni- tiomer.3 It is most often prescribed to treat arthritis, fever, menstrual symptoms, and pain. The required * To whom correspondence should be addressed. Phone: intakes of ibuprofen can be minimized by improving its 61-2-9385-4341. Fax: 61-2-9385-5966. E-mail: N.Foster@ effectiveness in terms of increasing the dissolution rate unsw.edu.au. in the biological environment. 10.1021/ie000151a CCC: $19.00 © 2000 American Chemical Society Published on Web 12/04/2000 Ind. Eng. Chem. Res., Vol. 39, No. 12, 2000 4795 It is well recognized that the dissolution rate of drugs P is the operating pressure, Φ2 is the solute fugacity in the gastrointestinal fluids is generally the rate- s coefficient, and v2 is the solute molar volume. determining step in the absorption of drugs rather than The Peng-Robinson equation of state (PR EOS) is their diffusion rates across the gut wall. However, the commonly used to evaluate the fugacity coefficient at in vivo dissolution rate and the availability of a drug high pressure.9 The objective of this modeling was to for gastrointestinal absorption from solid dosage forms provide a mathematical description of the measured are difficult to determine. In vitro dissolution rate data, which can be used to interpolate the solubility at experiments are generally performed instead.4 other conditions. In this study, the feasibility of the RESS technique Solute physical properties, such as critical tempera- for the micronization of poorly water-soluble ibuprofen ture (Tc), critical pressure (Pc), and acentric factor (ω), was investigated. Prior to the RESS experiments, an for high molecular weight compounds are not commonly investigation of ibuprofen solubility in supercritical CO2 available. The group contribution techniques such as 10,11 (SC CO2) was required. The solubility of racemic ibu- Joback, Ambrose, and Lydersen have been employed profen in SC CO2 was measured using a dynamic to estimate solute physical properties. The vapor pres- apparatus for pressures between 80 and 220 bar and sure of ibuprofen and its molar volume were estimated temperatures of 35, 40, and 45 °C. The solubility data by the methods presented by Lyman et al.11 The was modeled using the Peng-Robinson equation of state interaction parameter (kij) was assumed to be a function with van der Waals mixing rules. The solubilities of (S)- of temperature and was varied to obtain the best fit of ibuprofen and (R)-ibuprofen were also determined at 35 the experimental data. A PASCAL program was written °C within the pressure range of 80-200 bar. The RESS to optimize kij by minimizing the average absolute experiments involved an investigation of the effects of relative deviation (AARD) using the golden search the pre-expansion pressure, spraying distance, and method.12 The AARD that was used as an objective nozzle length on the size and morphology of the par- function was calculated by the following equation, ticles. The dissolution kinetics of the particles in a phosphate buffered solution were also determined. Two - 1 ypred yexpt different dissolution tests, powder dissolution and disk AARD ) Σ| | (2) intrinsic dissolution, were employed to investigate the N yexpt effect of size reduction and degree of crystallinity on the dissolution kinetics of ibuprofen. where N is the number of experimental data, ypred is Solubility data are essential for an accurate experi- the solubility predicted by the model, and yexpt is the mental design and for calculation of the concentration experimental data. of supercritical solutions at different RESS operating conditions. Solubility data for ibuprofen in SC CO2 at Materials and Methods 50 °C has been reported by Estevez and Suleiman.5 However, no information regarding the phase behavior Materials. Racemic ibuprofen (Sigma, 99.8% purity), (S)-(+)-ibuprofen (Aldrich, 99% purity), (R)-(-)-ibupro- of ibuprofen in CO2 nor solubility data at other iso- therms were reported. fen (RBI, 99% purity) were used as received. Carbon dioxide (BOC Gases, 99.95%) was used as the solvent. McHugh and Krukonis6 found that some solid organ- Phosphate buffer (Sigma, 8.3 mmol/L, pH 7.2) was used ics may exhibit melting-point (or freezing-point) depres- for preparing the mobile phase for HPLC analysis. sions when compressed in the presence of a supercritical fluid (SCF). As the pressure increases, the solubility of Potassium phosphate monobasic (Sigma, 99% purity) the SCF in the solute phase increases, resulting in lower and sodium hydroxide (Sigma, minimum 98% purity) temperatures being required to freeze the solute. The were used to prepare phosphate buffer solution for the degree of melting-point depression is dependent on the dissolution studies. solubility of the SCF in the solute phase. If the solubility Melting-Point Depression Studies. A study of the of the SCF is large, the melting-point depression will melting-point depression of racemic ibuprofen and its be significant. Melting-point depression has been ob- enantiomers was carried out using a static technique. A glass tube (i.d. ) 5 8 mm) loaded with the solute was served in several binary systems, such as CO2- 7 placed inside the view cell (Jerguson sight gauge series naphthalene and CO2-octacosane. In this study, the phase behavior of racemic ibuprofen and its enantiomers No. 32). The system was placed in the constant tem- was examined prior to the solubility measurements perature water bath. Carbon dioxide was gradually fed being conducted. into the view cell at 3 bar increments.