Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 1998. / Includes bibliographical references (p. 215-236). / by Gregg B. Nyberg. / Ph.D.

Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemical Engineering, 2015. / Cataloged from PDF version of thesis. / Includes bibliographical references (pages 164-184). / With the cost to discover and develop a drug now estimated to exceed $2 billion, the pharmaceutical industry is in search of innovative and cost-effective ways to reduce process footprint, minimize lead times, and accelerate scale-up. One path to achieving these goals is in the adoption of continuous processing. Among the many advantages offered by the use of continuous flow systems is the ease of integration of automation and online analytics for realtime monitoring of reactions. The further incorporation of feedback into automated systems invents an even greater possibility: the use of algorithms to intelligently manipulate different continuous variables-for instance temperature, time, and concentration-until an optimal synthesis is achieved. This thesis opens by reviewing the most recent applications of feedback optimization in flow. The same methodology is then applied to the estimation of reaction kinetics in a series-parallel SNAr reaction network. Unfortunately, the most challenging aspect of reaction development tends not to necessarily be the continuous variables, but rather the enumerate combinations of discrete variables-e.g. catalysts, ligands, and solvents-that, when paired with the continuous variables, give rise to changes in the reaction mechanism or kinetics. To address this problem, this thesis introduces a more general approach to reaction optimization with the construction of an automated segmented flow system, wherein reactants are confined to sub-20 [mu]L slugs flowing through a heated Teflon tube microreactor and analyzed online by LC/MS. The system allows for manipulation of both discrete and continuous variables, making it possible to simultaneously screen reagents while optimizing the reaction. A sequential adaptive response surface methodology for optimizing both discrete and continuous variables is presented. The algorithm employs optimal design of experiments in feedback to greatly accelerate convergence of the mixed integer nonlinear programming (MINLP). Examples of real-time simultaneous screening and optimization are explored, including optimal solvent selection in a selective alkylation reaction and optimal palladacycle-ligand precatalyst selection for Suzuki-Miyaura cross-coupling reactions. We conclude by showing how the automated system can be utilized to gain further understanding of reaction mechanisms and kinetics and by demonstrating that the optimal results can be scaled to larger chemical syntheses. / by Brandon Jacob Reizman. / Ph. D.

Thesis (M.S.) Massachusetts Institute of Technology. Dept. of Chemical Engineering, 1947. / Bibliography: leaf 95. / by Allan L. Bralove. / M.S.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2013. / This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections. / Cataloged from student-submitted PDF version of thesis. / Includes bibliographical references. / In this work, we are motivated by the need to produce particles of well-controlled size, shape and morphology for general application in catalysis, environmental remediation, nanomedicine, pharmaceuticals, the development of new materials, and other fields. Moreover, our approaches are guided by the desire for continuous and scalable production, in contrast to the batch-wise processes typically used. We employ the emulsion droplet solvent evaporation method, which is extremely versatile, to create, for example, magnetic nanoparticles, polymeric Janus beads, and crystalline particles. The emulsion droplets act as confined spaces, or templates, within which the particles can form. Upon removal of the solvent, primary magnetite nanoparticles pack into dense magnetic clusters, polymers precipitate as beads, or small molecules crystallize out of the solution to form spherical particulates. The thesis is comprised of experimental, theoretical and computational work that discusses the control of polymeric Janus bead morphology; demonstrates the potential of various operations for integration into large-scale manufacturing systems for monodisperse particle production; and offers insight into solvent and particle diffusion during the solvent evaporation process. The formation of Janus beads by solvent evaporation-induced phase separation of polymer blends is studied using a model system of polystyrene (PS), poly(propylene carbonate) (PPC) and chloroform. The phase separation of the polymer solutions in the bulk is analyzed and a phase diagram is constructed. PS/PPC Janus beads of varying composition are synthesized and we demonstrate the ability to tune the morphology by varying the type and concentration of the surfactant. Thermodynamic models that describe the particle morphologies as functions of the interfacial tensions are discussed. The remainder of the thesis focuses on the development and characterization of continuous, high-throughput synthesis methods for functional particles based on solvent evaporation techniques. We introduce membrane emulsification and pervaporation as operations that have the potential to be integrated into such a process. We develop a population balance model to describe the transport of solvent from nanocrystal- or polymer-laden droplets in an emulsion as it flows through a pervaporation unit. The solvent transport is simulated using a high-resolution finite volume algorithm, which affords a smooth solution with second-order accuracy. The simulations provide information regarding the evolution of the particle size distributions and the diffusional behavior of the droplets. Furthermore, the required fiber length to remove the solvent completely from an emulsion can be determined in terms of natural dimensionless constants that arise from the structure of the model equations, making the model useful as a design tool. For systems with a high Biot number, we show that a lumped capacitance assumption, which greatly simplifies the model and reduces the computational requirement, is valid. Finally, we investigate the evaporative crystallization of glycine and alanine, and the clustering of magnetite nanocrystals, in emulsion films flowing down an inclined plane. The temperature and the solvent evaporation configuration are shown to have a significant effect on the transport behavior of the solvent and droplets. The potential of the inclined plane system in particle production is established, and the flow of emulsion droplets of different sizes is studied, using an experimental test apparatus. / by Emily P. Chang. / Ph.D.

Thesis (Ph.D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 1999. / Includes bibliographical references (leaves 130-137). / by Jennifer Tsengjian Chin. / Ph.D.

Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemical Engineering, 2017. / Cataloged from PDF version of thesis. / Includes bibliographical references (pages 123-141). / Nanoeinulsions (or nano-scale emulsions) are gaining importance in diverse areas like drug delivery, development of smart food drinks, personal care, advanced material synthesis and pharmaceutics. They possess attractive properties such as high surface area, robust stability and tunable rheology. There are two broad categories of method to prepare nanoemulsions: high energy and low energy methods. The literature lacks a mechanistic understanding of nanoemulsion formation leading to a trial and error approach. In this thesis, we address this issue by providing a rationale to synthesize nanoemulsions for both high energy and low energy methods. Specifically, we develop a new scaling theory for high energy methods to control the droplet size of nanoemulsions by taking into account the effect of Ohnesorge number, a parameter that quantifies the internal viscous effects of the droplet. We validate the scaling theory with a wide range of experimental data for different nanoemulsion systems prepared from two high energy techniques. Our experimental results are in good agreement with the predictions and demonstrate the importance of including Ohnesorge number. The proposed relation also compares favorably with the experimental data from literature. We also develop a new droplet breakage frequency model that builds on the scaling theory, and use it in a population balance model to predict the kinetics of droplet size change. The predicted kinetics is consistent with our experimental data as well as data from literature. For low energy methods, we identify that the current understanding in literature in not complete since it not consistent with the existing experimental trends. We propose that migration of surfactant to the interface is the critical step for nanoemulsion synthesis and show that the proposed mechanism works for several model systems. These results thus provide a more general route to synthesize nanoemulsions and open up possibilities that were previously overlooked. Based on our understanding, we exploit low energy methods for use in pharmaceutical formulations and nanoparticle synthesis. Droplets entrapped in a mnicrochannel have potential to serve as a platform for drug discovery, diagnostics, material synthesis and reaction engineering. Current methods in literature require a prior step to generate droplets and do not allow for flexibility in controlling the morphology of droplets. We overcome these limitations by developing a method that uses sequential injection of oil and water over photo-patterned obstacles. By changing the shapes and arrangement of obstacles, we are able to control the morphology of entrapped liquid. We also model the volume of liquid entrapped through geometrical arguments and explain the mechanism of entrapment process. We successfully validate our predictions by experimentally varying the parameters like wetting and shape of the obstacles. We also examine entrapment in patterned side-walls and study the effect of pattern amplitude and frequency. / by Ankur Gupta. / Ph. D.

Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemical Engineering, 2017. / Cataloged from PDF version of thesis. / Includes bibliographical references (pages 109-123). / Current protocols for immune system monitoring involve the collection of cells from blood or cerebrospinal fluid. However, since major populations of immune cells reside within tissues, these invasively-obtained body fluid samples are, at best, indirect indicators of the status of the immune system. Direct tissue sampling through biopsies is difficult to incorporate into long-term, repetitive, longitudinal immune monitoring. Whereas delayed-type hypersensitivity tests (e.g., Mantoux tuberculin test) query the presence of antigen-specific cells in the skin, but do not provide information about the phenotype and functional characteristics of responding immune cells. Here we present a technology that addresses several of these challenges simultaneously, with the synergistic goals of providing enhanced diagnostic methods for sampling and analyzing the function of the immune system, and providing a greater insight into the status of the immune system than state-of-the-art assays. We designed hydrogel-coated, immune-monitoring, sampling microneedles that are capable of sampling non-recirculating immune cell populations present in the skin and permitting the quantification of biomarkers present in collected dermal interstitial fluid, thus enabling the parallel monitoring of both cellular and humoral immune responses. We focused, first, on optimizing the materials for fabricating sampling microneedles with the requisite properties of mechanical integrity and robustness, reproducible fabrication, effective skin penetration, ability to include bioactive cell-signaling molecules in the MN sampling platform and a compartment within the platform for sample collection and retention. Next, we utilized two animal models: an immunization model in which mice were vaccinated with model antigen ovalbumin, and an infection model in which mice were infected, via tail-skin scarification, with vaccinia-virus expressing SIVgag. We established that including adjuvants and antigen as cargo in lipid nanocapsules embedded in the hydrogel coating of the microneedles elicit the recruitment and sampling of not only antigen-specific cells, but also non-recirculating tissue resident memory cells. In both models, we demonstrated that even at long times post antigen exposure, sampling microneedles consistently recruited for higher proportions of antigen-specific cells than those present in blood. Finally, we also showed that the dermal interstitial fluid collected via sampling microneedles, could be reliably quantified for biomarkers such as antigen-specific IgG. The technology of sampling microneedles allows ex vivo analysis of cells retrieved directly from the local tissue environment and enables the investigation of antigen-specific cells for diagnostic purposes as well as answering spatio-temporal questions related to immunology in local tissue environments. This simple, painless and minimally-invasive sampling approach should facilitate longitudinal monitoring of antigen-specific immune cell populations in the skin relevant for a variety of infectious and autoimmune diseases, and aid the process of vaccine design. / by Anasuya Mandal. / Ph. D.

Thesis (Sc. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 1937. / Vita. / Includes bibliographical references (leaves 113-115). / by Margaret H. Hutchinson. / Sc.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2005. / Includes bibliographical references. / High level ab initio quantum mechanical calculations were used to determine the intermolecular potential energy surface between argon and water, corrected for many- body interactions, to predict monovariant and invariant phase equilibria for the argon hydrate and mixed methane-argon hydrate systems. A consistent set of reference parameters for the van der Waals and Platteeuw model, ... and ..., were developed for Structure II hydrates and are not dependent on any fitted parameters. Our previous methane-water ab initio energy surface has been recast onto a site-site potential model that predicts guest occupancy experiments with improved accuracy compared to previous studies. This methane-water potential is verified via ab initio many-body calculations and thus should be generally applicable to dense methane-water systems. New reference parameters, ... and ..., for Structure I hydrates using the van der Waals and Platteeuw model were also determined. Equilibrium predictions with an average absolute deviation of 3.4% for the mixed hydrate of argon and methane were made. These accurate predictions of the mixed hydrate system provide an independent test of the accuracy of the intermolecular potentials. / (cont.) Finally, for the mixed argon-methane hydrate, conditions for structural changes from the Structure I hydrate of methane to the Structure II hydrate of argon were predicted and await experimental confirmation. We present the application of a mathematical method reported earlier' by which the van der Waals-Platteeuw statistical mechanical model with the Lennard-Jones and Devonshire approximation can be posed as an integral equation with the unknown function being the intermolecular potential between the guest molecules and the host molecules. This method allows us to solve for the potential directly for hydrates for which the Langmuir constants are computed, either from experimental data or from ab initio data. Given the assumptions made in the van der Waals-Platteeuw model with the spherical-cell approximation, there are an infinite number of solutions; however, the only solution without cusps is a unique central-well solution in which the potential is at a finite minimum at the center to the cage. / (cont.) From this central-well solution, we have found the potential well depths and volumes of negative energy for sixteen single-component hydrate systems: ethane (C₂H₆), cyclopropane (C₃H₆), methane (CH₄), argon (Ar), and chlorodifluoromethane (R-22) in structure I; and ethane (C₂H₆), cyclopropane (C₃H₆), propane (C₃H₈), isobutane (C₄H₁₀), methane (CH₄), argon (Ar), trichlorofluoromethane (R-1 1), dichlorodifluoromethane (R-12), bromotrifluoromethane (R-1 3B 1), chloroform (CHC1₃), and 1,1,1,2-Tetrafluoroethane (R-134a) in structure II. This method and the calculated cell potentials were validated by predicting existing mixed hydrate phase equilibrium data without any fitting parameters and calculating mixture phase diagrams for methane, ethane, isobutane, and cyclopropane mixtures. Several structural transitions that have been determined experimentally as well as some structural transitions that have not been examined experimentally were also predicted. In the methane-cyclopropane hydrate system, a structural transition from structure I to structure II and back to structure I is predicted to occur outside of the known structure II range for the cyclopropane hydrate. / (cont.) Quintuple (Lw-SI-SII-Lho-V) points have been predicted for the ethane-propane-water (277.3 K, 12.28 bar, and Xeth,waterfree = 0.676) and ethane-isobutane-water (274.7 K, 7.18 bar, and Xeth,waterfree = 0.81) systems. A two-fold mechanism for hydrate inhibition has been proposed and tested using molecular dynamic simulations for PEO, PVP, PVCap, and VIMA. This mechanism hypothesizes that (1) as potential guest molecules become coordinated by water, form nuclei, and begin to grow, nearby inhibitor molecules disrupt the organization of the forming clathrate and (2) inhibitor molecules bind to the surface of the hydrate crystal precursor and retards further growth along the bound growth plane resulting in a modified planar morphology. This mechanism is supported by the results of our molecular dynamic simulations for the four inhibitor molecules studied. PVCap and VIMA, the more effective inhibitors, shows strong interactions with the liquid water phase under hydrate forming conditions, while PVP and PEO appear relatively neutral to the surrounding water. / by Brian Anderson. / Ph.D.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 1996. / Includes bibliographical references (leaves 223-246). / by Justin Hanes. / Ph.D.