Production of Nanoparticles and Microparticles by Evaporative Precipitation into Aqueous Solution (EPAS)
Life Sciences : Drug Delivery
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- Robert Williams III, Ph.D. , College of Pharmacy
- Keith Johnston, Ph.D. , Chemical Engineering
- Timothy Young , Chemical Engineering
- Xiaoxia Chen, Ph.D. , Chemical Engineering
Nearly half of the new chemical entities identified by drug discovery programs are rejected as product candidates due to poor water solubility. The safety and efficacy profiles of many poorly water-soluble drugs on the market are often compromised by poor or erratic bioavailability. Simply increasing dosing to achieve effective serum levels introduces a greater risk of toxicity.
The industry has employed various strategies to improve bioavailability, including the synthesis of more soluble derivatives, the use of surfactants and excipients, conjugation, and reduction in particle size by grinding and milling. These approaches may alter the chemistry of the drug substance, introduce additional toxicities, or fall short of the needed reduction in particle size.
Several methods have been developed in recent years to create nanoparticles with the surface area, morphology and wetting ability to enable rapid dissolution and better absorption. Nanoparticle size may also be exploited for targeted delivery to certain organs, tissues or cell types. Common techniques for nanoparticle and microparticle production include precipitation with a compressed fluid antisolvent (PCA) and rapid expansion from supercritical to aqueous solution (RESAS).
EPAS is a method for preparing highly potent, rapidly dissolving particles of poorly water-soluble drug particles. The method comprises dissolving a drug in at least one organic solvent to form a drug/organic mixture, atomizing the drug/organic mixture into an aqueous solution containing stabilizers, and concurrently rapidly evaporating the organic solvent in the presence of the aqueous solution to form an aqueous dispersion of the drug particles.
The rapid evaporation of solvent results in a very high supersaturation and a rapid nucleation of particles. Particle growth and size is controlled by the use of stabilizers. The resulting drug particles are in the nanometer to micrometer size range with meta crystallinity or an amorphous structure. The particle size distribution is monodisperse.
University of Texas at Austin investigators and their collaborators have formulated several drugs using EPAS and have demonstrated the desired potency, morphologies, and dissolution properties. High concentrations of nanoparticles of intraconazole created by EPAS have been delivered to the lungs of mice by nebulization. Nanoparticles of intraconazole delivered by this route have proven effective in treating Aspergillus infections.
- Very high potency, in some cases over 90%
- Control of particle size
- Control of size distribution
- Ability to minimize particle agglomeration
- Collected at atmospheric pressure, unlike PCA
- Avoids use of superfluids common in RESAS
Pharmaceuticals to overcome solubility barriers for new chemical entities (NCEs) and for product cycle management; food and nutritionals