Micronization by Rapid Expansion of Supercritical Solutions to Enhance the Dissolution Rates of Poorly Water-Soluble Pharmaceuticals

Abstract

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.

Micronization of Phenylbutazone by Rapid Expansion of Supercritical CO₂ Solution

“…For the purpose of micronization, some active pharmaceutical ingredients, such as salicylic acid, 7,8) griseofulvin, 9) ibuprofen, 9,10) have been used. The mean particle size of the drugs obtained by the RESS technique drastically reduced to micron order.…”

Application of dense gas techniques for the production of fine particles

“…Although the SEM images showed that the particles were aggregated, they were easily dis- persed upon ultrasonification in water as confirmed by the results of particle size distribution measured by Malvern Mastersizer. 7 Process parameters such as temperature, pressure, and nozzle design did not significantly influence the ibuprofen precipitate characteristics. The composition of enantiomer in racemic ibuprofen was 1:1 and did not change while processed by the RESS technique.…”

“…The details of the experimental technique have been described previously. 7 ASES: The schematic diagram of the ASES apparatus is presented in Figure 2. Micronization by the ASES process was conducted by first pressurizing the precipitation vessel to the desired pressure and then allowing the CO 2 to flow through the vessel from the top.…”

Mass transport model through the skin by microencapsulation system

“…Moreover, in previous studies about the variation of solubility of the ibuprofen versus time [29] , it is demonstrated that its solubility increases exponentially in the time. Due to the hydrophobic nature of ibuprofen, the aggregation of ibuprofen powders is obtained during the dissolution testing [29]. And, in this study, there is a good dispersion of the ibuprofen, because, basically, this takes part of a microencapsulation system, thus avoiding the aggregation of the active agent.…”

“…According to the literature [26,[28][29][30], the solubility of ibuprofen in a phosphate buffer solution (receptor fluid) at a temperature of 37 °C and pH = 7.4 is 6.02 mg/mL. However, ibuprofen has a very low water solubility (0.14 mg/mL), and in the lipophylic layer (SC) the ibuprofen release is slower than in the hydrophilic domain (epidermis-dermis).…”