Browsing by Subject "Modeling and Simulation"

Now showing 1 - 3 of 3
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    Advanced modeling of nanoparticle nucleation: towards the simulation of particle synthesis
    (2012-11) Liu, Jun
    Nanotechnology holds a lot of promise for the discovery of new phenomena, and many of the envisioned processes involve nanoparticles. These particles are found in chemical sensors, drug targeting and delivery, and one important application is motivated by the need of clean renewable energy sources. Gas-to-particle conversion in the form of homogeneous nucleation within flow systems plays a significant role in a variety of natural and industrial processes of nanoparticle synthesis. In this work, nucleation processes of several metal materials and dibutyl phthalate (DBP) nanoparticles in laminar and turbulent flows are investigated via direct numerical simulations (DNS). The flows consist of condensing vapor diluted in argon or nitrogen issuing into a cooler particle-free stream. DNS facilitates probing the interactive effects of fluid dynamics and nucleation in an accurate manner. The fluid, thermal and chemical fields are obtained by solving the Navier-Stokes, enthalpy, and mass transport equations. Nucleation is simulated via calibrated classical homogeneous nucleation models. Recently developed size dependent surface tension model offers increased accuracy in predicting metal particle nucleation. This approach is attractive in that it promises to be more accurate than the classical nucleation theory while maintaining much of its simplicity when coupling with fluid dynamics. The effects of turbulence on metal nucleation are also studied using fully resolved DNS to elucidate the effects of different stages of fluid mixing on metal particle nucleation. The effects of nucleation on fluid dynamics are investigated via DNS of DBP nucleation within both laminar and turbulent jet flows. The simulations provide a demonstration of how heat release affects the interactions of fluid dynamics and nucleation at different Reynolds numbers and particle formation rates. The results provide insights into the interaction of fluid, thermal transport and nanoparticle nucleation in various flows, which stimulate development of models that will allow engineers to optimize the fluid and thermal environments for industrial nanoparticle production. For brevity, specific conclusions are provided in each chapter.
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    Modeling of Concentrated High Intensity Electric Field (CHIEF) and Its Comparison with Other Non-thermal Liquid Food Pasteurization Technologies
    (2015-12) Peng, Peng
    Non-thermal preservations of food have received rising attention due to the increase concern of environmental sustainability and the demand of safer food with improved nutritional functionalities. High pressure and electric field treatment are two non-thermal food treatment strategies that have been widely studied. Some representatives of non-thermal technologies that utilize high-pressure and electric field to pasteurize food products include High hydrostatic pressure (HHP), high-pressure homogenization (HPH), and pulsed electric field (PEF). These non-thermal technologies, together with concentrated high intensity electric field (CHIEF) are studied and compared in this thesis research. This study used finite element (FEM) and computational fluid dynamics (CFD) methods to model and simulate the fluid flow, electric field distribution and temperature rise in CHIEF reactor. The simulation was confirmed to be valid by comparing it with experimental results. The model built in this study showed that the performance of CHIEF system was influenced by a set of intrinsic and extrinsic parameters. This model could be used to control and set variables in further optimization of the CHIEF system. Each of the non-thermal technologies discussed in this study has its advantages and unique field of use. HHP, dynamic high-pressure treatment and PEF are relatively mature technologies, while CHIEF system is an innovative and promising non-thermal method that can potentially be used as alternative to PEF.
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    Quantitative Pharmacological Approaches for Characterizing Lamotrigine Pharmacokinetics in Special Populations of Pregnancy, Postpartum and Breastfeeding Infants to Prospectively Optimize Dosing
    (2020-12) Karanam, Ashwin
    Lamotrigine (LTG) is one of the most prescribed antiseizure medications (ASMs) in women with epilepsy during pregnancy and postpartum. Pregnancy-related physiological changes are expected to alter LTG pharmacokinetics (PK) especially increases in apparent clearance (CL/F), leading to subtherapeutic concentrations and in-turn potential loss of efficacy and/or safety. This necessitates increases in LTG dose during pregnancy to maintain therapeutic LTG concentrations followed by a postpartum reduction in dose to prevent toxicity. In addition, infants born to mothers on LTG therapy are exposed to LTG via breastmilk, necessitating quantitative characterization of rate and extent of LTG exposure in infants and possible relationships with infant neurocognitive and developmental outcomes. Management of LTG therapy in pregnancy and postpartum is thus balancing seizures in mother while minimizing LTG exposure to fetus and infants. These special populations are understudied especially with respect to PK-pharmacodynamic (PK-PD) relationships. This dissertation work aims at characterizing changes to LTG PK in pregnancy, postpartum and in breastfeeding infants. In addition, this thesis explores feasibility of potential LTG dosing algorithms which maximizes exposure and safety during pregnancy. The long-term goal of this research work is to create robust evidence-based guidelines for dosing LTG in both pregnant women with epilepsy and their breastfeeding children.Investigations into CL/F changes in early pregnancy were performed in women with epilepsy maintained on LTG monotherapy who were planning to become pregnant. CL/F increased at the rate of 0.115 L/h for every gestational week with increases in CL/F observed as early as 5 weeks gestational age, often before women themselves know they are pregnant, and continue to increase through gestational week 13. The average increase in clearance by week 13 was approximately 1.6 times the preconception CL/F. Such rapid increases in LTG-CL would necessitate dose-adjustments relatively early in pregnancy. It was also identified that LTG-CL increased by 0.844 L/h for every 1 ng/ml of estradiol however gestational age was a more robust predictor of LTG-CL changes. This may potentially be due to gestational age reflecting additional factors, although neither was robust enough for clinical use owing to significant interpatient variability. We also identified a subpopulation of women who may not experience significance CL/F changes in early gestation however quantification of this group was limited by the small sample size. Our findings highlight the importance of planning and early detection of pregnancy and use of therapeutic drug monitoring (TDM) in this population. LTG CL/F changes in pregnancy and postpartum necessitate dose changes. However, there exists no consensus on dosing recommendations for these populations. Simulation based methods were used to understand the outcomes of LTG dosing changes and different regimens in pregnant women with epilepsy (PWWE) based on published data. We identified that without any dose changes women in the high CL/F change group could experience loss of efficacy as early as 8 weeks gestational age. At least two dose increases during pregnancy would be needed to prevent loss of efficacy. However, using the same two dose increase strategy in women with low CL/F change during gestation could possibly lead to toxic/unsafe LTG concentrations. These results show that a “one size fits all” philosophy does not work well for LTG dosing in PWWE based on current knowledge and reinforces the need for TDM. LTG CL/F was characterized in the largest cohort of PWWE and nonpregnant women with epilepsy (NPWWE) enrolled in the MONEAD study. During pregnancy, we identified two subpopulations of women that exhibited different rates of increase in LTG CL/F. The gestational age associated increase in CL/F displayed a 1.75-fold increase in pregnancy at the end gestation in a majority of the PWWE (91%) compared to no identifiable change in LTG CL/F in the remaining 9% closely reproducing a previous study performed in a smaller population. Clinical covariates available in the study failed to explain the difference in subpopulations. We anticipate genotypic variations in the activity or induction of UGT1A4 or polymorphisms in estrogen receptors could partly explain the varying degrees of enhanced CL/F between the two groups of pregnant women and may warrant further investigation. In the postpartum period, LTG CL/F reached baseline values by 3 weeks after birth necessitating dose tapering early in postpartum. After 3 weeks, the CL/F in postpartum PWWE was indistinguishable from NPWWE CL/F confirming that pregnancy related changes do not carry over to postpartum. Infant LTG exposure via breastmilk was quantified in breastfeeding infants exposed to LTG enrolled in the MONEAD study. Median infant LTG concentrations were approximately 28.9% of maternal concentrations with a range of 0.6-90.3% indicating significant infant exposure but also wide between infant variability pointing out the need to accurately characterize infant LTG PK. A physiology-based PK model (PBPK) methodology was utilized to incorporate mechanistic information of LTG disposition in both postpartum mother and infants to characterize LTG exposure with both models having predictions within 1.6-fold of observed levels. These models provide mechanistic understanding of LTG-CL changes in infants and predictions of infant exposures which can be used for exploring exposure-neurocognitive developmental relationships. This PBPK model serves as a framework for understanding PK and quantifying exposure of other commonly used drugs in these special populations and is not limited to the epilepsy therapeutic area. Overall, the studies presented in this thesis characterized the LTG PK in special underrepresented populations of women with epilepsy and their infants including pregnancy and postpartum and breastfed infants. The results of this thesis add robust evidence to inform clinical management of LTG therapy in PWWE.