Nanoparticles (clean and in suspension)

There is intense activity focused on the synthesis and characterization of nanoparticles, nanocoatings, and nanopatterned surfaces. Essential examples include * Fabrication of microelectronic devices where, for example, the density of surfaces features controls the storage capacity of memory chips and the speed and energy consumption of microprocessors. * Manufacture of ceramics where the ability to intimately mix nanoparticles determines the quality of the finished product. * Synthesis and processing of nanopharmaceuticals where the ability to control the size and state of agglomeration of nanocrystals determines their behavior in the human body. Interaction forces between micron-sized particles is well described by the potentials of Johnson, Kendall and Roberts (JKR), or Derjaguin, Muller and Toporov (DMT). Both models are based on an earlier analysis by Hertz, who considered two elastic bodies in contact under an external load but ignored attractive interparticle forces. In the JKR approach, the effective steady state pressure in the contact circle is assumed to be the superposition of elastic Hertzian pressure and of attractive surfaces forces, which act only on the contact area. DMT also considers non-contact forces in the vicinity of the contact area. However, for nanoparticles, the continuum elasticity breaks down, and the theory needs to be reformulated. A detailed atomic study is needed in order to determine the effective forces between nanoparticles. In fact, other kinds of forces are exceedingly important for nanoparticles, such as van der Waals forces, capillary bridges, and ion exchange forces. We investigate interaction forces for clean nanoparticles and nanoparticles in suspension using molecular dynamics simulations. In the case of nanosuspensions, our simulations include not only nanoparticles, but also solvent and surfactant molecules. We study stability of nanoparticles in various solvent/surfactant mixtures. All species in the system (solvent, surfactants and nanoparticles) are modeled ab initio from their constituent atoms, thus leading to the development of rigorous methods for understanding the effect microstructure and chemistry on macroscopic behavior of nanoparticles/surfactant/solvent mixtures.

Production and Stabilization of Pharmaceutical Nanosuspensions

The production and stabilization of pharmaceutical nanosuspensions has been a recent focus of the pharmaceutical industry where it has been shown that nanosuspensions of poorly water-soluble drugs exhibit a greatly increased dissolution rate, and as a consequence, an increased in vivo bioavailability. Accordingly, the ability to manufacture stable pharmaceutical nanosuspensions in a fast, safe, and predictable manner would be highly advantageous. However, the small size is not without consequence; the prodigious amount of available surface area in combination with van der Waals forces quickly cause irreversible agglomeration, destroying the desired properties, and thus requiring the use of surfactants for any combination of steric, electrostatic, and kinetic stabilization. As a result, this work focused on two distinct methods for producing pharmaceutical nanosuspensions, as well as the important role that surfactants play in stabilization. In the first method, high pressure homogenization was used to mill suspensions by forcing them through a minute piston gap, where particles were subjected to a combination of shear, cavitation, and grinding. This technique was optimized for use by incorporating excipients for novel formulations in situ with the goal of producing capsules, films, and oral-suspensions. Alternatively, the shortcomings present in all accepted nano-sizing methodologies led to the development of the emulsion precipitation method. In this process, nanoparticles as small as 60 nm were produced by extracting drug nanoparticles from an O/W emulsion made from partially miscible components. It was found that formulations utilizing any one of five contrastive solvents could be used to create nanosuspensions based not on intrinsic drug properties, but rather on droplet size, solvent diffusion, and surfactant choice, rendering this technique arguably the most robust currently available. Finally, the recurrent issue of stability was addressed through a series of molecular dynamics simulations and corresponding experiments to elucidate the molecular phenomena present at the surfaces of nano-scale crystals. Several case studies measured the interfacial binding energy between a surfactant and a crystal surface, where strong interactions were indicative of a longer shelf-life, quenched growth rates, and predictable crystal morphologies. It is hoped, that the culmination of this work will greatly advance our ability to produce, stabilize, and deliver poorly-soluble drug.