Browsing by Author "Needham, David"

This thesis addresses mass transfer in multi-phase single particle systems. By using a novel technique based upon the micropipette, the dissolution of liquid and gas droplets in a liquid medium can be observed. Three classes of experimental systems are observed: pure liquid droplet dissolution in a pure liquid environment, miscible mixture liquid droplet dissolution in a pure liquid environment, and solute-containing liquid droplet dissolution in a pure liquid environment. Experiments on the dissolution of pure droplets of water in n-alcohols and n-alkanes showed that water droplets dissolved ten times faster in the alcohols as compared to in the alkanes. When solubility was taken into account, however, and diffusion coefficients calculated using the Epstein-Plesset equation, diffusion constants for alkanes were twenty five times higher in alkanes than for the corresponding alcohol (for example 12.5 vs 0.5 x 10-8 cm2/s for pentane and pentanol). This difference in rates of diffusion of the single molecules reflects the effect of hydrogen bonding on small solute diffusion, which is expounded upon in Chapter 2.

A model for the dissolution of a droplet containing a mixture, each component of which is soluble in the surrounding liquid medium is presented in Chapter 3. The model is based upon a reduced surface area approximation and the assumption of ideal homogenous mixing : Mass flux (dm_i)/dt=〖Afrac〗_i D_i (c_i-c_s){1/R+1/√(πD_i t)}, where Afraci is the area fraction of component i, ci and cs are the initial and saturation concentrations of the droplet material in the surrounding medium, respectively, R is the radius of the droplet, t is time, and Di is the coefficient of diffusion of component i in the surrounding medium. This model was tested for the dissolution of ethyl acetate and butyl acetate in water and the dissolution of butyl acetate and amyl acetate in water, and was found to provide a good fit. In Chapter 4, a partial differential equation, R^2/D ├ ∂c/∂t┤|_η=(∝η)/D ∂c/∂η+(∂^2 c)/〖∂η〗^2 +2/η ∂c/∂η, is presented for the dissolution of a solute containing droplet in a liquid medium, and shell or bead formation is predicted. In Chapter 5, an application of the solute containing droplet dissolution is presented in which suspensions of glassified protein microspehres are used to improve the injectability of protein based pharmaceuticals. Injectability is related to viscosity, and the viscosity of a suspension may be predicted to follow the Krieger Dougherty equation: (η(Φ))/η_0 =(1-Φ/Φ_m )^(-2.5Φ_m ) , where Φ is the volume fraction of the suspensate, η is the viscosity of the overall suspension, η0 is the viscosity of the suspending fluid, and Φm is the maximum possible volume fraction. Finally, in Chapter 6, various experimental methods used to generate droplets are addressed.

This thesis presents an analysis of the material properties and phase behavior of divalent ionic surfactant salts, and protein and polymer glasses. There has been extensive interest in understanding the phase behavior of divalent ionic surfactants due to the many applications of ionic surfactants in which they come into contact with divalent ions, such as detergency, oil recovery, and surfactant separation processes. One goal of determining the phase boundaries was to explore the option of incorporating a hydrophobic molecule into the solid phase through the micelle-to-crystal bilayer transition, either for drug delivery applications (with a biologically compatible surfactant) or for the purpose of studying the hydrophobic molecule itself. The liquid micellar and solid crystal phases of the alkaline earth metal dodecyl sulfates were investigated using calorimetry, visual inspection, solubilization of a fluorescent probe, and x-ray diffraction. The Krafft temperature and dissolution enthalpy were determined for each surfactant, and partial composition-temperature phase diagrams of magnesium dodecyl sulfate-water, calcium dodecyl sulfate-water, as well as sodium dodecyl sulfate with MgCl₂ and CaCl₂ are presented. As a proof of concept, fluorescence microscopy images showed that it is, in fact, possible to incorporate a small hydrophobic molecule, diphenylhexatriene, into the solid phase.

The second, and main, part of this thesis expands on work done previously in the lab by using the micropipette technique to study two-phase microsystems. These microsystems consist of a liquid droplet suspended in a second, immiscible liquid medium, and can serve as direct single-particle studies of drug delivery systems that are formed using solvent extraction (e.g., protein encapsulated in a biodegradable polymer), and as model systems with which to study the materials and principles that govern particle formation. The assumptions of the Epstein-Plesset model, which predicts the rate of droplet dissolution, are examined in the context of the micropipette technique. A modification to the model is presented that accounts for the effect a solute has on the dissolution rate. The modification is based on the assumption that the droplet interface is in local thermodynamic equilibrium, and that the water activity in a solution droplet can be used to determine its dissolution (or dehydration) rate. The model successfully predicts the dissolution rates of NaCl solutions into octanol and butyl acetate up to the point of NaCl crystallization. The dehydration of protein solutions (lysozyme or bovine serum albumin) results in glassified microbeads with less than a monolayer of water coverage per protein molecule, which can be controlled by the water activity of the surrounding organic medium. The kinetics of dehydration match the prediction of the activity-based model, and it is shown how the micropipette technique can be used to study the effect of dissolution rate on final particle morphology. By using a stable protein with a simple geometry (lyosyzme), this technique was be used to determine the distance dependence of protein-protein interactions in the range of 2-25 Å, providing the first calculation of the hydration pressure decay length for globular proteins. The distance-dependence of the interaction potential at distances less than 9 Å was found to have a decay length of 1.7 Å, which is consistent with the known decay length of hydration pressure between other biological materials. Biodegradable polyesters, such as poly(lactide-co-glycolide) (PLGA), are some of the most common materials used for the encapsulation of therapeutics in microspheres for long-term drug release. Since they degrade by hydrolysis, release rates depend on water uptake, which can be affected by processing parameters and the material properties of the encapsulated drug. The micropipette technique allows observations not possible on any bulk preparation method. Single-particle observations of microsphere formation (organic solvent extraction into a surrounding aqueous phase) show that as solvent leaves the microsphere and the water concentration in the polymer matrix becomes supersaturated, water phase separates and inclusions initially grow quickly. Once the concentration in the polymer matrix equilibrates with the surrounding aqueous medium, the water inclusions continue to grow due to dissolved impurities, solvent, and/or water-soluble polymer fragments resulting from hydrolysis, all of which locally lower the water activity in the inclusion. Experiments are also presented in which glassified protein microbeads were suspended in PLGA solution prior to forming the single microspheres. This technique allowed the concentration of protein in a single microbead/inclusion to be determined as a function of time.

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