Ibuprofen And Myristic Acid Microparticles And Microcomposites Generated By A PGSS Process

Using supercritical fluids (SCFs) to manufacture microparticles/microspheres is a promising direction in chemical engineering, material science, pharmaceutical, and so on. SCF technology has some significant advantages over traditional methods, such as little environmental pollution, preferable particle morphology (PM), controllable particle sizes, and simple equipments. In order to obtain desired particles with small particle size (PS) and narrow particle size distribution (PSD), and/or microspheres with controlled release, several SCF-based techniques have been proposed in the past decades, among them, the particle formation from gas-saturated solutions (PGSS) process attracted great interest of lots of investigators due to several unique features. The studies of this thesis include two parts: study on solid-liquid-gas (SLG) phase equilibrium and generation of microparticles/microspheres by using PGSS. In the first part, an apparatus was established, the melting points of myristic acid and ibuprofen under high pressures of CO₂ and N₂ were measured, and the SLG phase equilibrium was theoretically investigated. In the second part, a PGSS experimental apparatus was improved, and the generation of ibuprofen and myristic acid microparticles and ibuprofen/lipid microspheres was investigated by using both CO₂ and N₂.A high-pressure apparatus with a view cell for determining the melting points of ibuprofen and myristic acid in CO₂ and N₂ was built; the capillary method was used. The measured data indicated that the melting points of myristic acid and ibuprofen decreased to 45°C and 36°C, respectively, with the increase of the CO₂ pressure; they kept almost unchanged after 10MPa. The melting points of the two substances had no change or slightly increased with the increase of the N₂ pressure. The SLG phase equilibrium for the ibuprofen-CO₂, myristic acid-CO₂, ibuprofen-N₂, myristic acid-N₂ systems were investigated using PR-NRTL model and GE-EOS model. The PR-NRTL model showed a good correlation with the experimental results through adjusting the NRTL-model parameters: the absolute average deviations (ADDs) between the correlated and experimental melting points of ibuprofen or myristic acid were 1.6K, 0.099K, 1.1K and 0.074K, respectively, for the ibuprofen-CO₂, ibuprofen-N₂, myristic acid-CO₂, and myristic acid-N₂ systems. The predictions of the GE-EOS model with the LCVM mixing rules showed a good agreement with the experimental data: ADDs were 1.2K and 0.88 K, respectively, for the ibuprofen-CO₂ and myristic acid-CO₂ systems. A different ADD (2.7K) was obtained for the latter system when using the other set of critical constants of myristic acid, indicating the sensitivity of the physical property to the SLG phase behavior.A PGSS apparatus was improved for using both CO₂ and N₂. Based on the SLG investigations, the particle generation of ibuprofen by using CO₂ revealed that needle-like particles or plates were produced in high-pressure region, while spherical particles could be found at relatively low pre-expansion pressures. The obtained SEM pictures showed that the average PS of processed particle was between 2 and 3μm. In the investigated ranges, it was found that a high pre-expansion pressure, a small nozzle diameter, or a low pre-expansion temperature favored producing small ibuprofen particles. When it comes to the myristic acid particles by using both CO₂ and N₂, spherical, needle-like and plate particles were obtained from the CO₂-assisted process, while hollow, spherical and relatively large particles were obtained in the case of using N₂. The average PS for particles from the CO₂-assisted and the N₂-assisted processes were 0.8-1.5μm and 5-8μm, respectively. The PS obviously decreased and the PSD became narrow when the pre-expansion pressure was increased; however, the pre-expansion temperature and the nozzle size showed no evident effect on the PS and PSD. Furthermore, the particle formation mechanism was proposed based on the XRD analysis of the produced ibuprofen and myristic acid particles.Based on the conditions and particles generated for pure ibuprofen and myristic acid, the ibuprofen/lipid microspheres were investigated by using both CO₂-assisted and N₂-assisted PGSS processes. The obtained microspheres containing 5% or 20% ibuprofen showed similar PM, PS and PSD of the myristic acid particles in the case of N₂-assisted process. Nevertheless, the microspheres from the CO₂-assisted process had a large PS and broad PSD, compared to that of the pure myristic acid particles. Although the XRD analysis of microspheres indicated that ibuprofen was successfully encapsuled by myrisitc acid, the ibuprofen dissolution rates from the produced microspheres revealed that either the microspheres from the N₂-assisted process or that from the CO₂-assisted process had attained no controlled release for ibuprofen. Tripalmitin in place of myristic acid was investigated; the obtained ibuprofen/tripalmitin microspheres containing 5% or 20% ibuprofen showed an evidently controlled drug release. For example, the drug release was only 20% in 500 min for the ibuprofen/tripalmitin microspheres containing 20% ibuprofen, prepared by the CO₂-assisted process.