Chapter 18
Nanoprecipitation of Pharmaceuticals Using Mixing and Block Copolymer Stabilization *
Brian K. Johnson, Walid Saad, and Robert K. Prud'homme Downloaded by YORK UNIV on July 7, 2012 | http://pubs.acs.org Publication Date: March 9, 2006 | doi: 10.1021/bk-2006-0924.ch018
Department of Chemical Engineering, Princeton University, Princeton, NJ 08544 Corresponding author:
[email protected] *
A new technology to form nanoparticles of hydrophobic organic actives at high concentration and yield, and methods to characterize the process are presented. In the Flash Nano Precipitation process, an organic active and an amphiphilic diblock copolymer are dissolved in an organic phase and mixed rapidly with a miscible anti-solvent to trigger precipi tation of the active with a narrow particle size distribution and controlled mean particle size (50-500 nm). The enabling components are a novel "analytical" (quantified mixing time) Confined Impinging Jets (CIJ) mixer for millisecond stream homogenization and amphiphilic diblock copolymers, which alter the organic nucleation and growth, provide steric stabilization for the particles, and offer a functional surface for the composite. Methods to quantify fundamental time scales of the process and their relation to component thermodynamics are provided. The technology is useful for applications in en hanced pharmaceutical delivery, dye preparation, and pesticide formulation.
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© 2006 American Chemical Society
In Polymeric Drug Delivery II; Svenson, S.; ACS Symposium Series; American Chemical Society: Washington, DC, 2006.
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Downloaded by YORK UNIV on July 7, 2012 | http://pubs.acs.org Publication Date: March 9, 2006 | doi: 10.1021/bk-2006-0924.ch018
Introduction The production of submicron particles of hydrophobic, water-insoluble organic compounds at high solids loading is important in applications involving pharmaceuticals, dyes, and pesticides. For pharmaceuticals, the rate of dissolu tion of hydrophobic compounds can be controlled by the particle surface area, and therefore, particle size. For drugs used in cancer therapy, the immature vasculature in the cancer tumor allows passive targeting of the drug i f particle sizes are in the range of 100-200 nm. In addition, all of the particles must be below 220 nm to allow sterile filtration. The color intensity for pigments and insoluble dyes increases with decreasing particle size, as does the resolution for ink jet printing applications. While it is relatively easy to produce small inorganic particles owing to their higher surface energy and charge stabilization, organics are significantly more difficult (I). In nanoparticale formation via direct precipitation, the short length scales and small mass of nanoparticles result in rapid formation (ms) and dissolution kinetics (ms to s) for individual particles. Creation of a tailored nanoparticle size distribution requires rapid processing for tight control of nucleation, growth, and equilibration (ripening). Our goal is to develop a process and the understanding required for producing nanoparticles of organic compounds at high solids concentration, high productivity, and low colloidal stabilizer content. We also wish to tailor the surface properties of the nanoparticles through the formation of unique composite organic and block copolymer nanoparticles. For example, we investigate particles with a surface presented to the human body of poly(acrylic acid), a mucoadherent for enhanced drug retention, or poly(ethylene glycol), known to extend the lifetime of particles in the blood stream. Here, we present and rationalize an avenue for the production of highly tailored nanoparticles to meet the above applications. Our approach comprises the Flash NanoPrecipitation process as described in Figure 1 (2,3). The process contains several key components, the first of which is a rapid mixing time smaller than the formation time, T \ fa for a nanoparticle. This corresponds to a Damkohler number for precipitation (Da ), which is the ratio of these two mixing times, and which should be 1 T V I 1 I I I T 1 1 10 15 20 25 30 35 40 mole% water in methanol
Downloaded by YORK UNIV on July 7, 2012 | http://pubs.acs.org Publication Date: March 9, 2006 | doi: 10.1021/bk-2006-0924.ch018
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Figure 5. Thermodynamics of diblock copolymer micellization for poly(butylacrylate)-b-poly(acrylic acid), (PBA-b-PAA), of various block lengths (in monomer units). As the copolymer concentration is increased, the step change in static light scattering intensity upon micellization identifies the C . The C was measured at 10-35
