Nanotech 2010

Manufacture of ultrafine drug particles via the Rapid Expansion of Supercritical Solution (RESS) Process using Taguchi approach

I. Asghari, F. Esmaeilzadeh
Shiraz University, IR

Keywords: deferasirox, iron chelator, nanoparticles, rapid expansion of supercritical solution, Taguchi method


A multitude of pharmaceutical substances are often insoluble or only slightly soluble in aqueous media and the application of oral or injectable drugs is often limited by its low bioavailability. Recently, there have been great interests in finding environmentally friendly and reliable means of producing fine particles of pharmaceutical products for applications in biomedical and pharmaceutical engineering. A promising method to improve the bioavailability of pharmaceutical agents is the Rapid Expansion of Supercritical Solutions (RESS). The first goal of this work was to explore the process conditions for the formation of submicron particles by RESS. The RESS-process was used successfully to produce ultrafine pharmaceutical substances. SC-CO2 can improve the solubility of poorly water-soluble drug substances using few or no organic solvents and with little or no heating. Particle size plays a vital role in ensuring high performance in processes involving organic and inorganic particulate materials. With iron chelation therapy, a chelating drug binds with free or “labile” iron in the blood and organs, which allows for removal of excess iron from the body. When multiple transfusions are repeatedly needed and phlebotomy is not possible, chelation therapy provides a means of controlling iron overload. Chelators may be categorized by their binding structures. Deferasirox (DFS), a tridentate chelator, requires two molecules for iron(III) coordination. Deferasirox is a high-specificity iron chelator that provides 24-hour coverage in a once daily oral dose. The bioavailability (the percentage of the drug absorbed compared to its initial dosage) is limited by this insolubility. Dissolution rate is a function of the surface area of the particles and solubility. Dissolution rate is a direct function of total surface area for a dispersed phase. The surface area increases inversely with the particle size according to the expression, Sv= 6/d, where Sv is the specific surface area and d is the average particle diameter. The design of engineered particulates in the form of nanoparticles, microparticles, microfibers, or microcapsules with narrow particle size distribution (PSD), mainly in the areas of pharmaceuticals . Supercritical carbon dioxide can be used as a clean medium and thus potentially replace traditional solvents in many industrial processes. Therefore carbon dioxide has been receiving increased attention in heat-sensitive and contaminant-free pharmaceutical processing. Currently, two common routes for particle formation in supercritical fluids are available: supercritical antisolvent process (SAS) and rapid expansion from supercritical solutions (RESS) . In the RESS process, a supercritical solution with dissolved solute is rapidly expanded through a well-designed micrometer sized nozzle to ambient conditions. This brings about appreciable supersaturation, produces fast nucleation and uniform crystal growth and hence small particles with a narrow size distribution.. Defrasirox particle formation via the RESS process was investigated in the present study. The RESS experiments were carried out in a broad temperature range (35-55 oC) and pressures at 150–200 bar. The performance of RESS under different conditions was evaluated by analyzing the particle characteristics. The effects of extraction pressure, extraction temperature, nozzle diameter, and spraying distance on the shape and size of the particles formed are discussed. Our results show that extraction pressure and extraction temperature can significantly affect the morphology and size of the precipitated particles. A statistical experimental design method (Taguchi method with L9 orthogonal array robust design) was implemented to optimize experimental conditions of the purpose. For the Taguchi design and subsequent analysis, the software named as Qualitek-4 was used. The appropriate orthogonal array for the experiment was determined by the software. A well designed experiment can reduce substantially the number of experiments required. Extraction pressure, Extraction temperature, nozzle diameter and spraying distance were considered as process parameters to be optimized by ANOVA. The main objective of ANOVA is to extract from the results how much variations each factor causes relative to the total variation observed in the result.
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