<div> <p>Guided by the continuous manufacturing paradigm shift in the pharmaceutical industry, the proposed thesis focuses on the implementation of an integrated continuous crystallization platform, the oscillatory baffled crystallizer (OBC), with real time process monitoring. First, by defining an appropriate operating regime with residence time distribution (RTD) measurements, a system can be defined that allows for plug flow operation while also maintaining solid suspension in a two-phase system. The aim of modern crystallization processes, narrow crystal size distributions (CSDs), is a direct result of narrow RTDs. Using a USB microscope camera and principal component analysis (PCA) in pulse tracer experiments, a novel non-contact RTD measurement method was developed using methylene blue. After defining an operating region, this work focuses on a specific process intensification technique, namely spherical crystallization.</p> <p>Used mainly to tailor the size of a final dosage form, spherical crystallization removes the need for downstream size-control based unit operations (grinding, milling, and granulation), while maintaining drug efficacy by tailoring the size of the primary crystals in the agglomerate. The approach for generating spherical agglomerates is evaluated for both small and large molecules, as there are major distinctions in process kinetics and mechanisms. To monitor the spherical agglomeration process, a variety of Process Analytical Technology (PAT) tools were used and the data was implemented for scale-up applications.</p> <p>Lastly, a compartmental model was designed based on the experimental RTD data with the intention of predicting OBC mixing and scale-up dynamics. Together, with validation from both the DN6 and DN15 systems, a scale independent equation was developed to predict system dispersion at different mixing conditions. Although it accurately predicts the behavior of these two OBC systems, additional OBC systems of different scale, but similar geometry should be tested for validation purposes.</p> </div> <br>

<p>Developments in the technology are followed by the methods and frameworks in industry to intensify the production of information, tools, goods, and services. This trend has been followed by the pharmaceutical industry which is highly regulated by administrations to meet the quality requirements of the drugs and produce more for cheaper in a shorter time. As the knowledge and understanding of crystallization systems have been increasing with the development of process analytical technology (PAT) tools, it is inevitable to use the experience and data coming with it to develop data-driven, better processes. In the light of these developments, Industry 4.0 has started becoming the new paradigm in pharmaceutical industry pushing the data-driven design of pharmaceutical processes. This thesis demonstrates the development and usage of a framework for data-driven, model-based design of pharmaceutical processes that fall in line with this latest paradigm shift. The proposed framework can be summarized in four levels showing the benefits of the collected data and model development. These levels are data collection from specially designed experiments, model writing, using the data collected from the first step to train the model, validation of the model to call it ‘Digital Twin’ of the process, using the digital twin for process design via in-silico design of experiments (DoE) or process optimization. The chapters in this thesis are different case studies that follow these steps for model-based process design. The systems studied are batch cooling crystallization with temperature cycling to produce a drug compound, batch cooling crystallization with integrated milling and temperature cycling for the shape optimization of the same drug compound from previous step, and hot melt extrusion for amorphization of another drug compound. In addition to demonstrating the development of the whole framework and its possible benefits in each chapter, Chapter 4 is the solely experimental proof of concept of a previous, more general model-based design of a mill integrated crystallization work.</p>

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This autoethnographic study presents a narrative of my lifelong yearning to pursue the practice of magic while concurrently managing the frustrations of being a public elementary school teacher. This study also presents sets of facilitating factors that enabled me to surmount personal, professional, and sociocultural challenges to rekindle my direction and purpose in life. The research questions guiding this study include the following: 1) What are the multiple levels of influence that have contributed to my desire to be a magician and leave the teaching profession? ; and 2) In the interrelation of the above context, how do I reignite my artistic passion and purpose? Using the Bronfenbrenner model of human ecology, this study explores multiple levels of influence spanning those from a sociocultural perspective to those of an inter- and intrapersonal nature.

published_or_final_version / Biochemistry / Doctoral / Doctor of Philosophy

published_or_final_version / Mechanical Engineering / Doctoral / Doctor of Philosophy

Iceland straddles the Mid-Atlantic Ridge and overlies a mantle hotspot. This tectonic setting produces voluminous tholeiitic magmas. Volcanism in Iceland is focussed along three neovolcanic spreading ridges. During the Holocene, the Eastern Volcanic Zone (EVZ) in southeast Iceland has been the most volcanically active and has been the site of several large (>6 km3) eruptions, including the only floodbasalt type eruption in recorded history, the 1783-84 Laki eruption. Three eruptions of large volume have been sampled for this study: the 1783-84 Laki eruption (15.1 km3); the 3,000-4,000 yBP Thjórsárdalur eruption (probably >4 km3); and the ~8,600 yBP Thjórsá eruption (>21 km3). The products of these eruptions have been analysed using a range of analytical techniques, with the specific aim of investigating crystallisation, degassing and mixing processes in the magma reservoirs that feed large eruptions. The Laki eruption has been the particular focus of this study. Samples from different parts of the lava flow show fine-scale variations in trace element concentrations and ratios. This compositional variation is not fully explained by fractional crystallisation processes, but is strongly controlled by crystal accumulation as whole-rock incompatible trace element concentrations show a linear, negative correlation with the mass fraction of crystals in the sample. Simple crystal accumulation models, however, fail to explain the compositional variation, and one explanation is that the homogeneous Laki melt mixed with varying proportions of a crystal mush that contained its own liquid. The results of thermobarometry calculations indicate that the erupted Laki liquid was in equilibrium with olivine, plagioclase and augite at 1-3 kb. Most of the crystals carried by the flow are too primitive to have crystallised from the erupted liquid and barometry calculations indicate that clinopyroxene crystallised at 3-7 kb. The majority of the large crystals hosted in the Laki basalt samples are therefore antecrysts that grew within the same magma plumbing system as the Laki carrier melt but are not in direct chemical equilibrium with it. This finding is verified by the fact that olivine crystals that are too magnesian to be in chemical equilibrium with the Laki whole-rock composition contain melt inclusions with average La/Yb values that are the same within error as the whole-rock values. The wide range of La/Yb values in melt inclusions hosted in the most magnesian (Fo86) olivine crystals in comparison to the least magnesian (Fo<74) indicates the initial variability of the Laki magma prior to concurrent crystallisation and extensive mixing, which acted to homogenise the carrier melt composition. The preservation of a wide range of La/Yb within the melt inclusions in comparison to the whole-rock composition, and a range of La/Yb values in different inclusions from the same crystal, indicates short timescales between melt inclusion entrapment and quenching during eruption. Melt inclusion studies also reveal the dissolved volatile content of the Laki magma at the onset of olivine crystallisation, although the majority of H2O concentrations have almost certainly been reset by low pressure diffusive exchange with the host crystal or surrounding magma. Comparison of the behaviour of volatiles with that of incompatible elements in the melt inclusions indicates that CO2 was degassing during olivine crystallisation, but S, F and Cl were not. New estimates of total volatile loading to the atmosphere during the eruption based on melt inclusion volatile concentrations show SO2 and HCl loading comparable to previous estimates, but higher HF loading. Mass balance calculations show that the observed H2O and CO2 concentrations of melt inclusions hosted in olivines in chemical equilibrium with the Laki whole-rock composition are ~50% and ~93% lower respectively than would be expected if no pre-eruptive degassing of the magma reservoir had occurred, meaning that pre-eruptive degassing of H2O and CO2 from the magma must have been significant. Lava flows from Thjórsá are more compositionally variable than those from Laki, and have different average major and trace element compositions. Compositional variation within the Thjórsá whole-rock composition is explained by a combination of source variation and fractional crystallisation, and, unlike Laki, is not strongly controlled by crystal accumulation.

No description available.

Thesis (Ph.D.)--University of Delaware, 2006. / Principal faculty advisors: Dionisios G. Vlachos and Raul F. Lobo, Dept. of Chemical Engineering Includes bibliographical references.