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My research focuses on investigating the impact of moisture-induced and oligomer-induced viscosity changes on OH-initiated oxidation of semi-solid aerosols,and the role of gas-liquid interfaces in regulating aqueous aerosol chemistry. Saccharides, which are a major constituent of aqueous atmospheric aerosols, are chosen as model molecules to form highly oxygenated organic aerosols. The experiments are performed using an atmospheric pressure flow-tube reactor with both online VUV-AMS (Vacuum-Ultraviolet Aerosol Mass Spectrometer) and offline GC-MS analysis techniques. The decay rates of saccharide are determined by measuring the loss signal of saccharide in the particle phase as a function of OH exposure (time-integrated total concentration of OH radical). A reaction-diffusion model is developed to interpret the observed kinetics behavior. These results highlight that the chemical transformation of semi-solid aerosols is kinetically limited by bulk diffusion and that of aqueous aerosol is dependent on surface-bulk partitioning. The kinetics of the OH-initiated oxidation of semi-solid monosaccharide particles are obtained over a range of relative humidity (RH) in order to investigate the impact of moisture-induced viscosity changes on the mechanisms of oxidative aging of semi-solid aerosols. The reactive uptake coefficient of monosaccharide ( increases by a factor of 2.4 as the surrounding RH is increased from 10% to 30%. A reaction-diffusion kinetic model with a constant diffusion coefficient is developed to investigate the impact of bulk molecule diffusion on kinetics behavior of semi-solid aerosols. This study suggests that the diffusion of the bulk reactant from the particle inner core to its surface is the rate-limiting step in oxidation of the semi-solid aerosols. In order to investigate the oligomer-induced viscosity changes on reactive properties of semi-solid aerosols, reactive uptake coefficients are measured over a range of monosaccharide:disaccharide molar ratio ranging between 1:1 and 4:1 at 30% RH. The reactive uptake coefficient of monosaccharide is found to decrease by a factor of 5 as the molar ratio changing from 4:1 to 1:1. The observed decay behaviors can be reproduced by using a simple compositional Vignes relationship to predict the composition-dependent diffusion coefficients of the saccharides. Simulation results suggest that a gradient diffusivity arises due to concentration gradients across the particle through heterogeneous oxidation of semi-solid particles. These findings illustrate the impact of bulk composition on reactant bulk diffusivity, which determines the rate-limiting step during the chemical reaction of semi-solid multi-component particles. For equimolar monosaccharide-disaccharide aqueous aerosols, the reactive uptake coefficient of monosaccharide is 5.02±1.12 and the reactive uptake coefficient of disaccharide is 0.39±0.10. Molecular dynamics simulations of the mixed aqueous solutions reveal the formation of a ~10 Å disaccharide exclusion layer below the water surface. The monosaccharide concentration is predicted to be low at the surface and to increase rapidly within the first 10 Å of the air-water interface. The observed decays are consistent with a poor spatial overlap of the OH radical at the interface with the disaccharide in the particle bulk. These findings highlight the critical importance of partitioning of bulk reactant at the gas-liquid interface in determining the reaction rate of reactive species in aqueous aerosols.

Abstract: Applications of Raman spectroscopy to respirable dosage forms are explored in this thesis. First, a high performance Raman system enabling low-frequency Raman signal detection is described and used for pharmaceutical sample analysis. Applications to species identification and solid state differentiation are presented, including solid phase identification and differentiation of glycopyrronium bromide and formoterol fumarate in pharmaceutical powders, and identification of active pharmaceutical ingredients, e.g., salmeterol xinafoate, fluticasone propionate, mometasone furoate, and salbutamol sulphate, as well as excipients, e.g., amino acids, in different formulations, are presented. For the first time, low-frequency shift Raman spectra of mannitol polymorphs were measured and used for solid phase identification. Unambiguous identification of two similar bronchodilator metered dose inhalers, Ventolin® HFA and Airomir®, was accomplished. The low-frequency shift Raman signals can be used for the analysis of crystallinity of small samples (< 5 mg) of respiratory dosage forms in a multi-component formulation matrix containing less than 3% by weight of the component of interest. Second, quantitative macro-Raman spectroscopy was applied to the analysis of bulk compositions of pharmaceutical drug powders. A custom designed dispersive macro-Raman instrument with a large sample volume of 0.16 µL was utilized to quantitatively evaluate the composition of multi-component powder samples extracted from commercial products. A Monte-Carlo model was developed to predict the minimum sample volume required for representative sampling from heterogeneous samples with variable particle size distributions and compositions. For typical carrier-free respirable powder samples the required minimum sample volume was on the order of 0.0001 µL to achieve representative sampling with less than 3% relative error. However, dosage forms containing non-respirable carriers, e.g., lactose, required sample volume on the order of microliter for representative measurements. Error analysis of the experimental results showed good agreement with the error predicted by the simulation. Finally, a low volume flow rate single-nozzle impactor was designed and manufactured for the collection of aerosols in the respirable range for subsequent macro-Raman characterization. The impactor utilized standard scanning electron microscopy stubs as the impaction plate, allowing easy removal and sample analysis. The impactor was designed to operate at a volume flow rate of 0.5 L/min, and included multiple stages to allow aerodynamic diameter measurements in the range from 0.6 µm to 10 µm. Preliminary tests showed satisfactory performance of the new impactor, which was capable of collecting a single dose (300µg) of respirable particulate drugs actuated from a commercial pressurized metered dose inhaler.