Dissertations / Theses: 'Chemical pharmaceutical'

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Brettmann, Blair Kathryn. "Electrospinning for pharmaceutical applications." Thesis, Massachusetts Institute of Technology, 2012. http://hdl.handle.net/1721.1/76480.

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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2012.
Cataloged from PDF version of thesis.
Includes bibliographical references (p. 133-149).
The pharmaceutical industry is currently shifting from batch to continuous manufacturing, and for downstream processes, this shift can reduce costs and improve quality provided the new unit operations are chosen properly. Electrospinning, a method of making nanofiber mats from solutions of an active pharmaceutical ingredient (API), polymer and solvent, has shown great promise for producing final solid dosage forms with minimal process steps. In this thesis, we explore the use of electrospinning to produce fiber mats containing either amorphous or crystalline API, aiming to develop the process such that it can be used for a wide variety of final drug products. Key to utilizing electrospinning to make these products is understanding the composition and behavior of the final fiber mats. For fibers containing amorphous API, this means it is essential to understand the level of mixing between API and polymer and the stability of the final product, and for fibers containing crystalline API, the crystal morphology and extent of dispersion within the polymer must be understood. The mixing level of amorphous API and polymer in fibers was analyzed using solid state nuclear magnetic resonance relaxation times. It was found that, for aliskiren/poly(vinyl pyrrolidone) and indomethacin/poly(vinyl pyrrolidone) formulations, the materials are intimately mixed following electrospinning, with no phase separation down to a 2-10 nm domain size. This was not the case for a 4:1 aliskiren:poly(vinyl pyrrolidone) formulation prepared by hot melt extrusion, an alternative method for co-processing API and excipients, as solid state NMR analysis showed phase separation with domains of 20-80 nm or larger. The same electrospun formulations were shown to be stable as solid solutions for 6 mo. when stored at 40°C in a desiccator, indicating that electrospinning is a viable method to produce physically stable formulations containing amorphous API. To produce fibers containing crystalline API, two methods were used. In the first, an API/polymer solution was electrospun using the same method as for producing fibers containing amorphous API. It was found that spinning with a crystalline polymer can result in crystalline API in the fibers, but the crystallinity ultimately depends on more than the polymer and API properties. Due to the complexity of using this method, we developed the second method, involving electrospinning a suspension of API crystals in the polymer/solvent solution. We demonstrated the feasibility of spinning particles of up to 10pm diameter using polystyrene beads and then applied the process to electrospin two different APIs, albendazole and famotidine. The electrospun mats contained crystalline APIs well-dispersed within the fibers and tablets prepared from the mats displayed a higher dissolution rate than fibers prepared from powder blends.
by Blair Kathryn Brettmann.
Ph.D.

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Tan, Li Ph D. Massachusetts Institute of Technology. "Heterogeneous nucleation of active pharmaceutical ingredients on polymers : applications in continuous pharmaceutical manufacturing." Thesis, Massachusetts Institute of Technology, 2015. http://hdl.handle.net/1721.1/101511.

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Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemical Engineering, 2015.
Cataloged from PDF version of thesis.
Includes bibliographical references (pages 92-105).
In this thesis work, we aimed to explore crystallization processes for small molecule API compounds based on engineered polymer surfaces that could be used in continuous manufacturing. First, we identified a library of polymers that can be used and selected PVA as the model polymer based on its solution and film properties. We also illustrated a rational approach for designing and fabricating PVA film surfaces for increasing heterogeneous nucleation rate of different compounds and enable polymorph selection. The design philosophy was to select prevalent angles between major faces of crystals according to a selection of compounds, and to create substrate surfaces with indentations that include these angles. Nucleation induction time trends showed that heterogeneous nucleation rates were accelerated by at least an order of magnitude in the presence of PVA due to the favorable interactions between the model compounds and the polymer. Nucleation rates were further increased for patterned substrates with matching geometries. Surface indentations with non-matching angles resulted in faster nucleation rates than flat films but slower than matching geometries because they only increased the effective area of the films and their roughness. X-ray diffraction was used to reveal faces that preferentially interacted with the PVA side chains and to deduce possible arrangement of solute molecules at the corners of the indentations. Combining X-ray data and morphology of the crystal product, we suggest that matching geometries on the substrate enhanced nucleation of compounds. In addition to enhancing nucleation rate, polymorph selection was possible in the presence of the polymer substrate to yield a higher percentage of thermodynamically stable gamma indomethacin. Offline Raman experiments and in-line morphology determination confirmed that polymorph control of the final crystal product via kinetic control of the nucleation process was viable. For the aspirin system, the 85 degree angle lead to the highest rate of nucleation; for the polymorphic indomethacin system, XRPD results showed that gamma form preferentially formed on the PVA films with 65 and 80 degree angles leading to the largest reduction in nucleation induction time. Kinetic Monte Carlo simulation showed that a crystallizer incorporating both nucleation and crystal growth in the absence of active mass transfer would have too small a throughput and too large a footprint to be useful. The main reasons were long average nucleation induction times and slow crystal growth in the absence of convection. A set of batch desupersaturation experiments showed that mass transfer limited growth dominate the crystal growth kinetics at low supersaturations when nucleation events were suppressed. An increase in the bulk fluid velocity increased the effective growth kinetics in the system when mass transfer kinetics dominated. Steady state modeling based on the first principle approach was performed using a combination of Navier Stokes Equations and diffusion-convection mass transport equations. The modeling result demonstrated that for mass transfer from a moving fluid to a stationary surface, a thin momentum and concentration boundary layer existed at the leading edge, which resulted in much higher local mass transfer rates. In the absence of momentum boundary layers, mass transfer could only occur via diffusion, which resulted in slow growth kinetics. The first principle model was used to derive dimensionless number correlations for the continuous crystallizer.
by Li Tan.
Ph. D.

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Costantino, Henry Raymond. "Stability of solid pharmaceutical proteins." Thesis, Massachusetts Institute of Technology, 1995. http://hdl.handle.net/1721.1/32674.

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Jiménez-González, Concepción. "Life Cycle Assessment in Pharmaceutical Applications." NCSU, 2002. http://www.lib.ncsu.edu/theses/available/etd-20020207-155355.

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In the present work, life cycle information is developed to provide environmental input into process development and chemical selection within the pharmaceutical industry. The evaluation at various stages of the development process for Sertraline Hydrochloride, an effective chiral antidepressant, was conducted. This evaluation included the Life Cycle Inventory (LCI) and further Life Cycle Assessment (LCA) to compare several synthetic routes and production processes of this pharmaceutical product. To complete the Sertraline analysis, a methodology to generate gate-to-gate life cycle information of chemical substances was developed based on a transparent methodology of chemical engineering process design (an ab initio approach). In the broader concept of an LCI, the information of each gate-to-gate module can be linked accordingly in a production chain, including the extraction of raw materials, transportation, disposal, reuse, etc. to provide a full cradle-to-gate evaluation. Furthermore, the refinery, energy and treatment sub-modules were developed to assess the environmental burdens related to energy requirements and waste treatment. Finally, the concept of a Á¤lean/Green Technology GuideÃ?was also proposed as an expert system that would provide the scientists with comparative environmental and safety performance information on available technologies for commonly performed unit operations in the pharmaceutical industry. With the expected future application of computer-aid techniques for combinatorial synthesis, an increase of the number of parallel routes to be evaluated in the laboratory scale might be predicted. Life cycle information might also be added to this combinatorial synthesis approach for R&D. This input could be introduced in the earlier stages of process design in order to select cleaner materials or processes using a holistic perspective. This life cycle approach in pharmaceutical synthesis is intended to facilitate the evaluation, comparison, and selection of alternative synthesis routes, by incorporating the overall environmental impact of routes.

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Pernenkil, Lakshman. "Continuous blending of dry pharmaceutical powders." Thesis, Massachusetts Institute of Technology, 2008. http://hdl.handle.net/1721.1/42945.

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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2008.
This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.
Includes bibliographical references (p. 269-279).
Conventional batch blending of pharmaceutical powders coupled with long quality analysis times increases the production cycle time leading to strained cash flows. Also, scale-up issues faced in process development causes delays in transforming a drug in research to a drug under commercial production. Continuous blending is as an attractive alternative design choice to batch process and is examined in this work. This work proposes to examine the feasibility of applying continuous blending in pharmaceutical manufacturing. Two kinds of blenders, a double helical ribbon blender and a Zigzag R blender were chosen as experimental systems representing high shear and moderate shear equipment. This work first focuses on developing a process understanding of continuous blending by examining the ow behavior of powders in experimental blenders using impulse stimulus response experiments and subsequent residence time distribution analysis. Powder ow behavior was modeled using an residence time distribution models like axial dispersion models. These ow behavior studies were followed by blender performance studies. The dependence of the mixing performance of the continuous blending system on different operational variables like rotation rates of mixing elements and raw material properties like particle size, shape and cohesion were studied. Mean residence time and time period of fluctuation in the concentration of active ingredient coming at the inlet were the two most important operational variables that affected blender performance. Larger particles and particles with less cohesion were seen to mix well with higher dispersion coefficients in a ribbon blender. A residence time distribution based process model for continuous blending was investigated and shown to depict the process well within experimental errors in determining the parameters of the residence time distribution model.
(cont.) The predictive capability of the process model was found to dependent on the scale of scrutiny of the powder mixture in the blender. Choosing the correct scale of scrutiny was demonstrated to be of critical importance in determination of blend quality. Growing pressures on pharmaceutical industry due to patent expirations has forced manufacturers to look beyond the US and EU for potential manufacturing locations in addition to invest in novel manufacturing methods and technologies. The capstone work in this thesis proposes a framework that managers of pharmaceutical and biologics manufacturing can utilize to identify critical issues in globalization of manufacturing and in making strategic manufacturing location decisions.
by Lakshman Pernenkil.
Ph.D.

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Givens, Rassoolkhani Brittany Estelle. "Engineering variable particles for pharmaceutical applications." Diss., University of Iowa, 2019. https://ir.uiowa.edu/etd/6950.

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Polymeric-based drug and gene delivery is advantageous for a number of reasons. Polymers can increase the circulation time of the cargo, protect the cargo from enzymatic degradation, and improve localization at the target site. The present work focuses on three different polymers for drug and gene delivery: poly-lactic-co-glycolic acid (PLGA), polyethyleneimine (PEI) and polystyrene-co-poly(N-isopropylacrylamide) (PS-co-NIPAM). Each of these polymers has a niche within the drug and gene delivery field, and each has its own advantages and disadvantages. Formulations were prepared using each of the aforementioned polymers with an ultimate goal of translating the formulations to clinical applications. The drug PD98059, which has been identified as a potential treatment following myocardial infarction or for leukemia, has been loaded into PLGA nanoparticles, microparticles, or pellets. Each of these formulations was characterized based on size and surface morphology, as well as the release rate of the PD98059. Additionally, an HPLC-UV method was developed for detecting PD98059 at low concentrations using the wavelength of maximum absorption. Included with this HPLC-UV method was a method for extracting PD98059 and an internal standard (7-hydroxyflavone) from murine plasma to promote future biodistribution studies. Formulations were also prepared using PEI and plasmid DNA (pDNA). PEI is a cationic polymer that can improve the circulation time and cellular uptake of pDNA compared with naked pDNA alone. The PEI-pDNA complexes (nanoplexes) were delivered to two endometrial cancer cell lines: Ishikawa H and KLE. The pDNA encoded for mutations to the PLAC1 gene, which is a potential onco-target for endometrial cancers using the CRISPR-Cas9 delivery system. The relative gene expression of PLAC1 was measured after transfection, as well as the relative cell viability. In the Ishikawa cells, there was no improvement in transfection efficiency (decrease in PLAC1 expression) incurred by the PEI, and the cells did not undergo decreases in relative viability. However, in the KLE cells there were large decreases in relative cell viability in response to the nanoplexes, which also made it difficult to determine relative gene expression following transfection. Transfection was also paired with a genotoxic engineered nanomaterial (ENM) to investigate how co-delivery of nanoplexes and ENMs may influence the efficacy of gene therapy. The relative viability of A549 and Ishikawa H cells indicated that co-delivery was less toxic to cells compared with mono-delivery of either agent. Furthermore, relative expression of the cell cycle regulating p53 gene was increased after 48 hours in Ishikawa cells that received as little as 10 µg/mL CuO ENMs. Further toxicity investigations of CuO ENMs, ZnO ENMs, and SiO2 ENMs were conducted in the two lung epithelial cell lines A549 and Beas-2B, which indicated that the A549 cells are more susceptible to changes in viability as a function of ENM dose than the Beas-2B cells. Furthermore, the A549 cells likely internalized the SiO2 ENMs through the caveolae-mediated endocytosis mechanism. The uptake and toxicity of PS-co-NIPAM microgels, which are a thermo-responsive polymer, was assessed in HepG2 liver adenocarcinoma cells, which was ~3 µg/mL total (maximum) for a 90 µg/mL dose. As such, the endocytosis mechanism could not be determined for these investigations. The results also indicated that these microgels did not induce any toxicity at 150 µg/mL after 24 hour exposure, which is promising for their development as a biocompatible delivery system. The overarching goal of this research was to use polymeric formulations, which are known to be both biocompatible and highly tunable, for improved drug and gene delivery. The breadth of applications in this thesis highlights the many potential applications of polymeric formulations, as well as the interdisciplinary advantages to using polymers as carriers for sustained- and/or controlled-delivery.

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McLoughlin, C. M. "Microwave drying of pharmaceutical and fine chemical molecules." Thesis, Queen's University Belfast, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.273046.

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Kilinkissa, Ornella Edlyne Youdaga. "Physical chemical properties of selected pharmaceutical co-crystals." Thesis, Cape Peninsula University of Technology, 2014. http://hdl.handle.net/20.500.11838/731.

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Thesis submitted in fulfilment of the requirements for the degree Magister Technologiae: Chemistry in the Faculty of Applied Sciences at the CAPE PENINSULA UNIVERSITY OF TECHNOLOGY 2014
The solid state modification of a given active pharmaceutical ingredient is a desired way to alter its physicochemical properties, such as solubility or bioavailability. The solubilitymelting point relationship of the ensuing co-crystal or salt is not fully understood. In this thesis, a series of model co-crystals and pharmaceutical co-crystals and salts of baclofen were investigated. The model co-crystals were prepared from 4,4’-bipyridine (BIPY) and 1,2-bis(4-pyridyl)ethane (ETBIPY) used as host compounds which were combined with a series of carboxylic acids as co-formers, such as p-toluic acid (PTA), rac-phenylbutyric acid (racPBA), racemic and S-phenylsuccinic acid (racPSA and S-PSA, respectively). In the second part, six new multicomponent crystals of baclofen (BAC, (RS) 4-amino-3-(4- chlorophenyl)-butanoic acid), were prepared with mono- and dicarboxylic acids: two pharmaceutical co-crystals obtained with benzoic acid (BAC•BA) and p-toluic acid (BAC•PTA) and four pharmaceutical salts with 1-hydroxy-2-naphthoic acid, (BAC+)(HNA-), oxalic acid, 2(BAC+)(OA2-), maleic acid, (BAC+)(MA-) and p-toluene sulfonic acid, (BAC+)(PTSA-)•IPA. The compounds prepared were analysed by single crystal and powder X-ray diffractometry, differential scanning calorimetry and their solubility was measured in water and ethanol. From the analysis of the model co-crystals it was concluded that their aqueous solubility is inversely related to the melting point values and this can be explained by packing features. Also, the introduction of a chiral building block, compared to its racemic counterpart, is a valuable way to limit the formation of the intermolecular interactions in the new multicomponent crystal and thus decrease the efficiency of the packing which eventually leads to lower melting points and better solubility. The analysis of the baclofen crystals suggests that a strong, robust and predictable hydrogen bonding network with a combination of molecular building blocks which show acceptable molecular flexibility is a good recipe for successful co-crystal design.

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Chan, Chun Wong Aaron. "Ultraselective nanocatalysts in fine chemical and pharmaceutical synthesis." Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:866296af-5296-4d2e-8e52-6499dacaef0f.

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Surface catalysed reactions play an important role in chemical productions. Developments of catalyst requiring high activity whilst improving on product selectivity can potentially have a profound effect in the chemical industry. Traditional catalyst modifications were focused on tuning the size, shape and foreign metal doping to form well defined metal nanoparticles of unique functionalities. Here, we show new approach to engineering of metal nanocatalysts via a subsurface approach can modify the chemisorption strength of adsorbates on the surface. Carbon modified nanoparticles were synthesised using glucose to stabilise Pd nanoparticles at a molecular level. Upon heat treatment, the carbonised glucose encapsulated the Pd nanoparticles with carbon atoms take residence in the octahedral holes (15 at.%). These materials were tested in liquid phase stereoselective hydrogenations of 3-hexyn-1-ol and 4-octyne. The former has importance in the fragrance industry towards the production of leaf fragrance alcohol. It was shown for the first time that the geometrically and electronically modified Pd with interstitial carbon atoms reduced the adsorption energy of alkenes, ultimately leading to higher reaction selectivity. Boron modified Pd nanoparticles was synthesised using BH₃.THF in the liquid phase. The material possess high B interstitial saturation (20 at.%), which can be synthesised for the first time below 100°C. These materials were tested in the liquid phase selective hydrogenation of various alkynes and 2-chloronitrobenzene, of which the latter has importance in the pesticides industry. Kinetic modelling on the hydrogenation of 4-octyne suggests these subsurface occupied B does play a pivotal role on increasing the reaction selectivity, as removal of these species lead to decreased selectivity. Au nanoparticles were synthesised and characterised using H¹³COOH NMR. The new liquid NMR characterisation method is successfully applied to examine the chemisorption strength of metal nanoparticles. An attempt to synthesise PVP capped B modified Pd nanoparticles with the above NMR characterisation was investigated. It is believed the examples of subsurface atom modifications as shown here may offer future catalyst developments in this area.

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Yu, Shen. "Roll compaction of pharmaceutical excipients." Thesis, University of Birmingham, 2013. http://etheses.bham.ac.uk//id/eprint/4137/.

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Roll compaction is commonly used as a dry granulation technique in the pharmaceutical industry to produce tablets for formulations sensitive to heat and moisture. This thesis reports systematic studies on the behavior of pharmaceutical excipients in associated unit operations (i.e. roll compaction, milling, tabletting), as well as their correlations. Roll compaction experiments were carried out using an instrumented roll compactor with a gravity feeding system. The influence of the process parameters, material properties and powder conditioning were investigated Ribbons produced in roll compaction were granulated using an oscillating mill to investigate the milling process. A first order kinetics equation was introduced to describe the mass throughput of the granules. Using positron emission particle tracking technique, which provided a measurement of instantaneous velocity and the location of the ribbons, two milling regions (i.e. impact and abrasion) involving distinct fracture mechanisms were identified. Tabletting of the granules was performed using a universal test machine. A reduction in the compressibility and compactibility of the granules compared to the feed powders, due to work hardening, was also observed. A method was introduced to determine the optimized process conditions for roll compaction and milling through a close examination of the correlation between the unit operations.

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Pore, Mridula. "Pharmaceutical tablet compaction : product and process design." Thesis, Massachusetts Institute of Technology, 2007. http://hdl.handle.net/1721.1/51623.

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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2009.
Includes bibliographical references.
This thesis explores how tablet performance is affected by microstructure, and how microstructure can be controlled by selection of excipients and compaction parameters. A systematic strategy for formulation and process design of pharmaceutical tablets is proposed. A modified nanoindenter method was used to test the mechanical behavior of diametrally compressed excipient granules. X ray micro computed tomography and Terahertz pulsed spectroscopy (TPS) and imaging (TPI) were used to analyze the microstructure of the tablet core and detect internal defects. Granule failure mechanisms are found to be consistent with tablet microstructure. MCC granules deform plastically when tested and X ray images show individual granules undergoing increasing deformation in tablets as higher compaction forces are used. A highly interconnected pore-structure limited tablet hardness and led to bursting behavior during dissolution. No effect of compaction force or speed was observed in dissolution profiles. Lactose granules fracture at strains less than 5%, forming monolithic structures with no evidence of initial granule shape or size. Pore size decreases as compaction force is increased for DCL 11 tablets. A decreasing pore size corresponds to increasing THz refractive index, tablet hardness and dissolution time. DCL 11 and DCL 14 tablets compacted under the same conditions have the same pore size distributions and hardness, although DCL 14 granules are weaker than DCL 11, and DCL 14 tablets dissolve up to four times slower than DCL 11 tablets. No difference was observed between the THz spectra of tablets made from the two grades of lactose.
(cont.) Further work is needed to understand the physical significance of the THz measurements. TPI can detect laminated tablets and is faster than X ray micro CT. In order to develop a rational design methodology, two key areas for future research are building a process model for compaction and developing quality testing methods that can be analyzed mechanistically. The capstone project explores strategic decision making for innovator firms and generic drug manufacturers in the period surrounding patent expiry. Statin products were used as an illustrative case of a pharmaceutical technology experiencing commoditization. A system dynamics model was used to simulate historic results and explore options for products still under patent protection. Current models of technology market dynamics apply to statins, but regulation and legislation play a large role in controlling market entry, leading to strong sequencing effects.
by Mridula Pore.
Ph.D.

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Abel, Matthew J. "Process systems engineering of continuous pharmaceutical manufacturing." Thesis, Massachusetts Institute of Technology, 2009. http://hdl.handle.net/1721.1/58446.

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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, February 2010.
Cataloged from PDF version of thesis.
Includes bibliographical references (p. 290-299).
Continuous manufacturing offers a number of operational and financial benefits to pharmaceutical companies. This research examines the critical blending step for continuous pharmaceutical manufacturing and the characteristics of continuous downstream pharmaceutical manufacturing systems. Discrete element method (DEM) simulations were used to develop novel insights into the mechanism of mixing for continuous blending of cohesive pharmaceutical powders and to examine the effects of particle properties, blender design and operating conditions on blend homogeneity. To place continuous blending into the context of pharmaceutical manufacturing, the scope of the analysis was expanded to process system models of continuous downstream pharmaceutical manufacturing. DEM simulations were used to study the mechanisms of mixing in the continuous blending of pharmaceutical powders. Diffusive mixing from the avalanching particles appears to be the dominant mechanism of mixing in both the axial and radial direction for the double helical ribbon blender. This result can guide the development of future continuous pharmaceutical powder blenders by optimizing the mixing elements to increase the amount of particles transported to a position where they can avalanche/flow and diffusively mix. A range of particle properties, blender designs and operating conditions were examined for their effects on flow behavior and blend homogeneity. Three particle properties were examined: particle size, polydispersity and cohesive force.
(cont.) Particle size was observed to be positively correlated to both flow rates and blend homogeneity. Polydispersity had no effect on flow rate and was negatively correlated to homogeneity. Cohesive force was negatively correlated to flow rate and had little to no effect on homogeneity. Two modifications of blender design were analyzed: changes in blender size and changes in shaft design. Blender size was observed to be positively correlated to flow rate and negatively correlated to homogeneity. The paddle shaft designs created a more homogeneous powder blend than the double helical ribbon shaft. Two operating parameters were also studied: rotation rate and fill fraction. Rotation rate was positively correlated to both flow rate and homogeneity. Fill fraction had the interesting result of being positively correlated to the absolute flow rate, but negatively correlated to the fill mass normalized flow rate. In addition, fill fraction has a clear negative correlation to homogeneity above fill fractions of 0.55, but is inconsistent for fill fractions lower than this. This research on particle properties, blender designs and operating conditions will help to guide the operation of continuous pharmaceutical blenders and the design of continuous pharmaceutical manufacturing systems. Process simulations comparing model batch and continuous downstream pharmaceutical manufacturing systems have quantified some of the potential size, cost and performance benefits of continuous processes. The models showed significant reductions in process equipment sizes for continuous manufacturing particularly in the blending step.
(cont.) This reduction in equipment size translates to capital cost (CAPEX) savings for both the continuous process equipment and manufacturing facilities. The steady state operation of continuous processing also reduces the labor requirements and gives the continuous processes an operating cost (OPEX) advantage over batch processes. This research has contributed to the understanding of continuous pharmaceutical powder blending and quantified some of the benefits of continuous downstream pharmaceutical manufacturing. This work is being continued by the Novartis-MIT Center for Continuous Manufacturing whose work is providing the foundation for future industrial scale pharmaceutical continuous manufacturing systems.
by Matthew J. Abel.
Ph.D.

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Batista-Navarro, Riza Theresa Bautista. "Information extraction from pharmaceutical literature." Thesis, University of Manchester, 2014. https://www.research.manchester.ac.uk/portal/en/theses/information-extraction-from-pharmaceutical-literature(3f8322b6-8b8d-44eb-a8cd-899026b267b9).html.

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With the constantly growing amount of biomedical literature, methods for automatically distilling information from unstructured data, collectively known as information extraction, have become indispensable. Whilst most biomedical information extraction efforts in the last decade have focussed on the identification of gene products and interactions between them, the biomedical text mining community has recently extended their scope to capture associations between biomedical and chemical entities with the aim of supporting applications in drug discovery. This thesis is the first comprehensive study focussing on information extraction from pharmaceutical chemistry literature. In this research, we describe our work on (1) recognising names of chemical compounds and drugs, facilitated by the incorporation of domain knowledge; (2) exploring different coreference resolution paradigms in order to recognise co-referring expressions given a full-text article; and (3) defining drug-target interactions as events and distilling them from pharmaceutical chemistry literature using event extraction methods.

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Hokputsa, Sanya. "Chemical and hydrodynamic investigations of polysaccharides with pharmaceutical importance." Thesis, University of Nottingham, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.289502.

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Qian, Zizheng. "Synthesis of pharmaceutical molecules using flow based chemical processing." Thesis, University of Cambridge, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.610172.

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Chen, Jie Ph D. Massachusetts Institute of Technology. "Computer-aided rational solvent selection for pharmaceutical crystallization." Thesis, Massachusetts Institute of Technology, 2010. http://hdl.handle.net/1721.1/59874.

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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2010.
Cataloged from PDF version of thesis.
Includes bibliographical references (p. 131-135).
Solvents play an important role in crystallization, a commonly used separation and purification technique in the pharmaceutical, chemical and food industries. They affect crystal properties such as particle size distribution, morphology, polymorphism etc. and therefore have consequences for the downstream processing of the solid material. Current solvent selection techniques for solution crystallization remain ad hoc and typically do not have a theoretical underpinning. Elucidation of the interactions between solvent and solute molecules and the mechanism underlying the solvent effects on each aspect of the crystal properties would be a major aid for the rational selection of solvents and also the development of crystallization processes. In this work we studied the effect of solvent on the polymorphism and morphology of organic crystals using molecular modeling techniques. The two most important contributions of this thesis are listed below. 1. We studied the self-assembly of solute molecules in solutions prior to nucleation for two polymorphic systems, tetrolic acid and glycine, using molecular dynamics simulations. We tested the existence of a link between the structure of the clusters formed in solution and the polymorphism of the crystals. Our results show that the link hypothesis succeeds in explaining the polymorph selection of tetrolic acid from different solvents. However it fails for glycine and thus should be used with caution. 2. We designed a computer-aided rational solvent selection procedure for improving the morphology of needle-like 2,6-dihydroxybenzoic acid form 2 crystal. We also experimentally grew 2,6-dihydroxybenzoic acid form 2 crystals using the solvent mixture suggested by computer simulations, which do exhibit reduced aspect ratios. This computer-aided selection procedure can not only quickly identify an effective solvent or solvent mixture, but also provide mechanistic understandings of the underlying chemistry. It can also be extended to improve the morphology of other needle-like organic crystals easily.
by Jie Chen.
Ph.D.

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Bell, Erin R. "Melt extrusion and continuous manufacturing of pharmaceutical materials." Thesis, Massachusetts Institute of Technology, 2011. http://hdl.handle.net/1721.1/65755.

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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2011.
Cataloged from PDF version of thesis.
Includes bibliographical references.
Melt extrusion is an alternative processing technique that operates continuously, reduces the total number of unit operations, allows for incorporation of difficult-to-process drug substances, and has the potential to achieve tablets of better quality and consistency compared to traditional methods. Thus, our goal was to evaluate melt extrusion as a viable processing alternative and expand our scientific knowledge such that we gain predictive capabilities of tablet characteristics, i.e., quality by design. This new knowledge will aid future process design thereby helping to reduce time and costs associated with pharmaceutical solid dosage form production. The residence time distribution for melt extrusion has been characterized using a single parameter model. When combined with assumed first-order reaction rate kinetics and an Arrhenius reaction rate constant, the model can accurately predict the amount of drug product lost to temperature driven degradation. The model prediction agreed well with experimentally determined fractional conversion. The physical stability of amorphous Molecule A was characterized using enthalpy of relaxation measurements. Molecular level rearrangements are the source of physical instability for the fragile glass forming Molecule A. The instability can be modified by introducing a second component, which contributes to the overall enthalpy change. Coating amorphous Molecule A tablets with a polyvinyl alcohol based coating material reduces moisture uptake during storage. The coating material preferentially uptakes water from the atmosphere, restricting moisture from entering the tablet core and causing premature dissolution or degradation. The dissolution behavior of Molecule A tablets can be tailored with the addition of water soluble materials. Dissolution rate constants for Molecule A tablets have been calculated for different formulations and can be used as a resource when designing new solid dosage forms with desired dissolution characteristics. A novel 100% Molecule A melt extrusion process has been created, reducing the number of overall unit operations and eliminating troublesome blending inconsistencies. An additional formulation that maintains the crystallinity of Molecule A by processing with polyethylene glycol below Molecule A's melting temperature is physically and chemically stable and ready for implementation in a continuous production line. The mixing achieved within the extruder for this formulation is sufficient to eliminate a pre-mixing unit operation.
by Erin R. Bell.
Ph.D.

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Farrell, E. "Microwave-assisted drying of regulated pharmaceutical and fine chemical compounds." Thesis, Queen's University Belfast, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.431608.

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Smith, Kenneth Baird. "Crystallisation of active pharmaceutical ingredients using ionic liquids." Thesis, University of Birmingham, 2015. http://etheses.bham.ac.uk//id/eprint/6039/.

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It is proposed that Ionic Liquids offer a new opportunity for exploration into a novel medium for processing Active Pharmaceutical Ingredients, particularly with respect to habit control and polymorphic form. A review of relevant literature relating to ionic liquids properties, commercial applications and current research has been summarised together with background into fundamental crystallisation theory. Crystallisations using thermal methods were employed at laboratory scale and the physical properties of the resultant powders were analysed and compared to commonly encountered crystal forms. For paracetamol it was found that the morphology of the crystals could be manipulated, producing in some cases, habits not reported for conventional organic solvent crystallisation. This was achieved through changing both the IL used and the saturation of the system whilst in all cases retaining the most stable polymorph. ILs ILs to be ‘designed’ for a given API but greater understanding of the interactions between IL and solute are required first. Properties such as increased solvation power, thermal stability, liquidus range and low vapour pressure bring a number of advantages when designing industrial crystallisations. However ILs also have a number of disadvantages including phase separation problems.

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Lin, Ben Chien Pang. "Exploration of parameters for the continuous blending of pharmaceutical powders." Thesis, Massachusetts Institute of Technology, 2011. http://hdl.handle.net/1721.1/65761.

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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2011.
Cataloged from PDF version of thesis.
Includes bibliographical references (p. 113-119).
The transition from traditional batch blending to continuous blending is an opportunity for the pharmaceutical industry to reduce costs and improve quality control. This operational shift necessitates a deeper understanding of the mixing process informed by particle dynamics and variable interdependencies. The thesis aims to establish a framework for characterizing and improving continuous pharmaceutical blending using a tiered experimental methodology and multivariate analysis. This parameter space exploration attempts to reconcile previous research within the context of cohesive pharmaceutical powders and develop general design principles for maximizing blender performance. A design of experiments was conducted to determine mixing performance with respect to three factors - physical design, operating parameters, and material properties. Multivariate analysis using projections to latent structures was employed to quantify the effect of raw and intermediate variables on the variance reduction ratio. Significant parameters identified included the choice of API, fill fraction, the number of blade passes, the mean residence time, the Bodenstein number, and the period of input feed fluctuations. The results highlight the importance of shear and radial mixing for cohesive powders, which suggest that one-dimensional axial models common in blending literature may not be a sufficient theoretical framework for pharmaceutical applications. The research yielded several insights into design principles for optimizing blending performance. Increasing mean residence time and radial mixing create more robust processing by reducing the impact of material properties and fluctuations in feed consistency. The variance reduction ratio can be improved in a cost-effective manner by determining the fill fraction which maximizes intermediate metrics such as space time, mean residence time, and the number of blade passes. Multivariate analysis was demonstrated to be a practical tool for parameter space optimization and a promising technique for characterizing the effect of material properties on processing.
by Ben Chien Pang Lin.
Ph.D.

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Quon, Justin (Justin Louie). "Crystallization process development and spherical agglomerates for pharmaceutical processing applications." Thesis, Massachusetts Institute of Technology, 2013. http://hdl.handle.net/1721.1/79322.

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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2013.
Cataloged from PDF version of thesis.
Includes bibliographical references (p. 102-107).
The control of crystallization steps is essential in the production of many materials in the pharmaceutical, materials, and chemical industries. Additionally, due to increasing costs of research and development, reductions in manufacturing costs by moving from batch to continuous manufacturing are necessary to sustain profitability of the pharmaceutical industry. Two different projects were researched to progress towards this goal. The first was the demonstration of a continuous manufacturing platform. The second goal was the development of new crystallization techniques. Two continuous crystallization processes were developed as part of a demonstration unit for continuous manufacturing of Aliskiren hemifumarate. The first process was an anti-solvent crystallization of an intermediate. The second process was a continuous reactive crystallization developed for the final product. The processes were able to crystallize the two compounds with both high yield (>90%) and purity (>99%). Population balance modeling was performed and experimental data were fit to the model to obtain kinetic parameters for crystal growth and nucleation for both systems. The models were used to optimize crystal purity and yield of the products. In addition, this thesis describes two separate projects involving spherical agglomerates. In the first study, acetaminophen was shown to crystallize significantly faster in the presence of spherical agglomerates of lactose than single crystal lactose. An epitaxy study and molecular dynamics simulations showed that the (141̄)/(001) pairing of faces showed coincident lattice matching and favorable energy interaction. Maximizing the number of substrate faces available for interaction increases the chance for a lattice match between the substrate and the crystallizing material which can be useful for controlling and increasing nucleation kinetics. Finally, water-in-oil emulsions were used to make composite spherical agglomerates with two components: a heterosurface, and a target compound that does not typically crystallize as spherical agglomerates on its own. The generated composite agglomerates were relatively monodisperse and were characterized using optical microscopy, scanning electron microscopy, x-ray powder diffraction, and differential scanning calorimetry. This technique could potentially be applied to other hydrophilic compounds, in particular water-soluble pharmaceuticals compounds, in order to change crystal morphology to spherical agglomerates in order to simplify downstream processing.
by Justin Quon.
Ph.D.

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22

Domike, Reuben Dumont 1979. "Pharmaceutical powders in experiment and simulation : towards a fundamental understanding." Thesis, Massachusetts Institute of Technology, 2004. http://hdl.handle.net/1721.1/28659.

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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, September 2004.
Includes bibliographical references.
(cont.) The DEM simulation was used to simulate the relative importance of cohesion and friction. For angle of repose simulations, increasing the cohesion increased the final angle in a consistent, linear fashion. Increasing the interparticle friction coefficient increased the final angle up to a critical friction coefficient. For the range of two dimensional simulations with the particles shaped as discs, this critical friction coefficient was about 0.30. Above this threshold, increasing the interparticle friction had no impact on the angle of repose. This suggests that for most pharmaceutical powders, the cohesion and shape are the most important particle properties. Case studies relating interparticle adhesion to labscale powder performance (flow and blends) were completed with two active pharmaceutical ingredients and a number of excipients. In all of the flow cases, the rank order of interparticle or intermaterial adhesion forces measured with AFM was exactly predictive of the rank order of ease of flow. Similarly, in all of the blending case studies, the rank order of adhesion force between the active pharmaceutical ingredient and the excipient was exactly predictive of the rank order stability of blends of the materials. The blend stability was quantified using an on-line, nondestructive, noninvasive light induced fluorescence (LIF) instrument. Separately, the LIF instrument was used to estimate the content of fluorescent drugs (caffeine and triamterene) in tablets by measuring the surface fluorescence. A theoretical description of the accuracy of the surface measurement to correctly estimate the total content in a tablet ...
The flow of fine powder has not been fully understood nor has it been predictable by current simulation techniques. With the use of atomic force microscopy (AFM), interparticle forces of attraction and interparticle friction forces between fine particles have been measured with unprecedented success. In a novel coupling of technologies, the microscopic interparticle force data was used in a discrete element model (DEM) simulation to predict the bulk powder flow in multiple geometries. Excellent agreement between the simulated angles of repose for both glass beads and a microcrystalline cellulose pharmaceutical excipient was obtained. Qualitative agreement between simulation and experiment of flow in a rotating box was also obtained for these materials. The ability to measure interparticle friction forces for non-spherical particles was a novel development. The presence of surface asperities was shown to be directly responsible for changes in friction force. Interparticle friction coefficients were established by varying the applied load between particles. The average interparticle friction between the cellulose particles was 0.44, double the value for glass beads. For both particle types, the population of measured friction coefficients was well represented by a normal distribution. Interparticle friction was also measured between lactose particles. However, the surfaces of the lactose particles smoothed under high applied loads and the measured friction coefficients were lower (an average value of 0.26) than the cellulose particles. The similar friction coefficients for glass beads and smooth lactose particles further suggest that the interparticle friction was strongly dependent upon the surface asperities.
by Reuben Dumont Domike.
Ph.D.

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Ngai, Samuel S. H. "Multi-scale analysis and simulation of powder blending in pharmaceutical manufacturing." Thesis, Massachusetts Institute of Technology, 2005. http://hdl.handle.net/1721.1/33720.

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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, September 2005.
"August 2005."
Includes bibliographical references.
A Multi-Scale Analysis methodology was developed and carried out for gaining fundamental understanding of the pharmaceutical powder blending process. Through experiment, analysis and computer simulations, microscopic particle properties were successfully linked to their macroscopic process performance. This work established this micro-to-macro approach as a valid way to study unit operations in the pharmaceutical manufacturing of solid dosage forms. The pharmaceutical materials investigated were anhydrous caffeine, lactose monohydrate and micro- crystalline cellulose (MCC). At the macroscopic level, blending experiments were conducted in mini-scale lab blenders using the Light-Induced Fluorescence (LIF) technique. Effects of operating parameters on blending kinetics were systematically evaluated. It was found that the time required to reach a homogeneous mixture (thg) increased with blender fill volume (FV) and decreased with blender rotation rate (RPM). It was also found that MCC, as an excipient, always took longer time to mix with caffeine than lactose. At the microscopic level, force interactions - cohesion/adhesion and friction - were measured directly at the single particle level with Atomic Force Microscopy (AFM).
(cont.) It was found that cohesion/adhesion and friction fell into lognormal distributions. Based on AFM force maps, these distributions were attributed to the particle surface morphology. Chemically modified AFM cantilever tips were used to probe the hygroscopicity on the particle surfaces. In addition, the cohesive/adhesive forces were found to be size- dependent and thus, were converted to JKR surface energies to eliminate this dependence. Amongst the materials tested, MCC showed the strongest cohesive/adhesive and friction interactions. The AFM-measured microscopic force interactions were used to explain the blending kinetics profiles observed in the blending experiments. The longer blending time (thg) required by MCC was linked to its strong cohesive nature. In addition to these multi-scale relations, the AFM force interactions were used in Discrete Element Method (DEM) models for simulating blending processes. A two-dimensional model was used to simulate blending in a circular blender. With respect to the effect of operating parameters on blending kinetics, the simulations showed that thg increased as FV increased, RPM decreased, or when MCC as opposed to lactose was chosen as the excipient.
(cont.) These trends were identical to experimental observation. A three dimensional DEM code was developed. Blending in a V-shaped blender was simulated and results were consistent with experiments, namely the flow behavior correlated well with the differences in cohesion/adhesion and friction intensities of the excipients. Through a fundamental understanding at a microscopic level, one can identify opportunities for process improvement. In this way, Multi-Scale Analysis will facilitate the ability of pharmaceutical companies in pursuing the desired quality-by-design state in manufacturing.
Samuel SH Ngai.
Ph.D.

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Pu, Yu Ph D. Massachusetts Institute of Technology. "Theoretical and experimental investigation of particle interactions in pharmaceutical powder blending." Thesis, Massachusetts Institute of Technology, 2007. http://hdl.handle.net/1721.1/38962.

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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2007.
Includes bibliographical references.
In pharmaceutical manufacturing practices, blending of active pharmaceutical ingredient (API) with excipients is a crucial step in that homogeneity of active ingredient after blending is a key issue for the quality assurance of final products. Inadequate knowledge of the interdependence between raw material properties and their impact on the blending process often gives rise to product variance and failure and therefore higher manufacturing costs. Since particles are the basic unit of powder flow, a fundamental understanding of the crucial particle characteristics and particle interactions is essential for a good prediction and control of the blending process. In this work, inter-particle adhesion forces including van der Waals force, capillary force and electrostatic force of lactose monohydrate and microcrystalline cellulose were measured by the atomic force microcopy and other techniques. Their correlations with particle properties and environmental variables were elucidated quantitatively through mathematical modeling, and their impacts on powder blending homogeneity were investigated experimentally. It was found that surface roughness, electrostatic surface charges, moisture sensitivity as well as relative humidity are crucial parameters to determine inter-particle adhesion forces.
(cont.) By controlling these factors, the inter-particle adhesion forces can be optimized to improve final blend homogeneity. For instance, using excipient particles processed with surface-smoothing method reduced the blending time to reach endpoint. It was also found that enhancing electrostatic attractive interactions between excipient and API particles resulted in better blend homogeneity. In addition, the mathematical force models developed in this study allowed us to predict the magnitudes of inter-particle adhesion forces, which can be later used as an important input parameter in simulating the powder blending process of different scales. The mechanistic knowledge of particle interactions and their dependence on particle properties through this study provides a theoretical foundation for a successful linkage between the micro-scale particle level and the macro-scale bulk powder flow behavior, enhances process understanding, and opens opportunities for process improvement.
by Yu Pu.
Ph.D.

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Jiang, Mo. "Pharmaceutical crystallization design using micromixers, multiphase flow, and controlled dynamic operations." Thesis, Massachusetts Institute of Technology, 2015. http://hdl.handle.net/1721.1/98708.

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Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemical Engineering, 2015.
Cataloged from student-submitted PDF version of thesis.
Includes bibliographical references (pages 198-214).
Crystallization is a key unit operation in the pharmaceutical industry. Control of crystallization processes can be challenging when undesirable phenomena such as particle attrition and breakage occur. This thesis describes the controlled crystallization of pharmaceuticals and amino acids for more efficient manufacturing processes and better efficacy of products. Crystallization equipment is designed so that (1) the undesirable phenomena do not occur at all, and/or (2) the phenomena that do occur are carefully controlled. One key strategy is to exploit dual-impinging jets and multiphase flow to decouple nucleation and growth so that they can be individually controlled. Various configurations of micromixers were designed to provide controlled nucleation. Based on the dual-impinging-jet (DIJ) configuration, a physical explanation was provided for the discovery that a cooling micromixer can generate small crystals of uniform size and shape. An alternative design replaces the micromixing with the application of ultrasonication to decouple nucleation and flow rates. Based on these nucleation methods, a novel continuous crystallizer is designed where the slurry flow is combined with an air flow to induce a multiphase hydrodynamic instability that spontaneously generates slugs where the crystals continue to grow. These slugs are well-mixed without having the mixing blades in traditional crystallizer designs that induce undesirable uncontrolled crystallization phenomena. Another key strategy is to increase the degrees of freedom in the dynamic operation of the crystallizers. In the slug-flow continuous crystallizer, extra degrees of freedom for control of the crystal growth are created by spatially varying the temperature profile along the tube. In a semi-continuous crystallizer configuration, continuous seeding using a DIJ mixer is combined with growth rate control in a stirred tank to experimentally demonstrate the manufacture of uniform-sized crystals. In addition, temperature-cycling experiments are designed in batch crystallizers to substantially change crystal shape with only a small number of cycles. Experimental validation confirms that the proposed crystallizer designs reduce production time and equipment cost by orders of magnitude while suppressing secondary nucleation, attrition, and aggregation/agglomeration-dominant but undesired phenomena that worsen the ability to control the properties of crystals produced by most existing crystallizer designs.
by Mo Jiang.
Ph. D.

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Salem, Daniel P. (Daniel Parker). "Carbon nanotube-based optical sensors for pharmaceutical applications : theory and experiment." Thesis, Massachusetts Institute of Technology, 2019. https://hdl.handle.net/1721.1/132735.

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Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemical Engineering, June, 2019
Cataloged from the PDF version of thesis.
Includes bibliographical references.
Semiconducting single-walled carbon nanotubes (SWCNTs) are attractive transducers for biosensor applications due to their unique photostability, single molecule sensitivity, and ease of multiplexing. Sensors can be rendered selective via several detection modalities including the use of natural recognition elements (e.g., proteins) as well as the formation of synthetic molecular recognition sites from adsorbed heteropolymers. However, to date, deployment of SWCNT-based biosensors has been limited. The aim of this thesis was to study the design and development of SWCNT-based optical sensors for analytes relevant to the food and pharmaceutical industries including neurotransmitters, proteins, and metal ions. The research described in this thesis spans several levels of nanosensor development including: i) the fundamental study of SWCNT-polymer interactions and their dependence on solution properties; ii) sensor development using existing detection modalities and the use of mathematical modeling to guide sensor design and interpret data; and iii) the invention of a new sensor form factor enabling long-term sensor stability and point-of-use measurements. Our fundamental work on SWCNT-polymer interactions investigates the influence of polymer structure, SWCNT structure, and solution properties on molecular recognition, using single-stranded DNA as a model polymer system. We find that specific ssDNA sequences are able to form distinct corona phases across SWCNT chiralities, resulting in varying response characteristics to a panel of biomolecule probe analytes. In addition, we find that ssDNA-SWCNT fluorescence and wrapping structure is significantly influenced by the solution ionic strength, pH, and dissolved oxygen in a sequence-dependent manner. We are able to model this phenomenon and demonstrate the implications of solution conditions on molecular recognition, modulating the recognition of riboflavin. These results provide insight into the unique molecular interactions between DNA and the SWCNT surface, and have implications for molecular sensing, assembly, and nanoparticle separations. In addition to our experimental work, we used mathematical modeling to guide sensor design for biopharmaceutical characterization. A mathematical formulation for glycoprotein characterization was developed as well as a dynamic kinetic model to describe the data output by a label-free array of non-selective glycan sensors. We use the formulated model to guide microarray design by answering questions regarding the number and type of sensors needed to quantitatively characterize a glycoprotein mixture. As a second example, we report the design of a novel, diffusion-based assay for the characterization of protein aggregation. Specifically, we design hydrogel-encapsulated SWCNT sensors with a tunable hydrogel layer to influence the diffusion of immunoglobulin G protein species of variable size, and we develop a combined model that describes both the diffusion of analyte and analyte-sensor binding. By measuring the sensor response to a series of well-characterized protein standards that have undergone varying levels of UV stress, we demonstrate the ability to detect protein aggregates at a concentration as low as one percent on a molar basis. Finally, we report the development of a new form factor for optical nanosensor deployment involving the immobilization of SWCNT sensors onto paper substrates. We find that SWCNT optical sensors can be immobilized onto many different paper materials without influencing sensor performance. Moreover, we pattern hydrophobic barriers onto the paper substrates to create 1-dimensional sensor arrays, or barcodes, that are used for rapid, multiplexed characterization of several metal ions including Pb(II), Cd(II) and Hg(II). In addition to providing a new form factor for conducting point-of-use sensor measurements, these findings have the potential to significantly enhance the functionality of SWCNT-based optical sensors by interfacing them with existing paper diagnostic technologies including the manipulation of fluid flow, chemical reaction, and separation.
by Daniel P. Salem.
Ph. D.
Ph.D. Massachusetts Institute of Technology, Department of Chemical Engineering

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Hogan, Iain T. D. "The chemical regulation of carcinogenesis." Thesis, University of Bath, 1985. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.355115.

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The work outlined in this thesis is concerned with the use of chemical agents in the prevention and cure of cancer. Under this generally broad brief, we examined three topics of considerable interest in this field at the present time. Firstly we investigated the role of three dietary indoles which have been shown to inhibit the induction of cancer by certain procarcinogens, in particular benzo[a]pyrene. In this work we prepared analogues of the dietary indoles with a view to ascertaining their mode of action and increasing their activity. Next we devised a synthesis of dendrodoine, a natural product extracted in small quantities from the marine tunicate, Dendroda Grossular. This compound was shown in preliminary tests to be of potential use as a cytotoxic anti-cancer drug, but because of its inaccessibility its chemical synthesis was required if its properties were to be fully investigated. Finally, we devised a new strategy in the synthesis of 6H-pyrido-[4,3-b]carbazoles. Although there has been a great volume of work carried out on these compounds over the last 25 years, there has yet to be devised a truly general synthetic route, which allows the function- alisation of these compounds at key points in their structure.

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Bhuiyan, A. K. M. M. H. "A comparative study of chemical based skin mimics with pharmaceutical applications." Thesis, University of Huddersfield, 2016. http://eprints.hud.ac.uk/id/eprint/31498/.

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The prediction of percutaneous absorption is of enormous importance for the effective design, development and quality assessment of topical and transdermal formulations. In vitro diffusion experiments are widely carried out for such predictions and are of substantial interest across the pharmaceutical and cosmetic industries. Human or animal skin, usually excised, are often used in in vitro drug diffusion studies. However, difficulties in obtaining the mammalian skin and variation in their permeability directed researchers towards using synthetic membranes as skin mimics in preformulation screening experiments, where a large number of experiments are required. Polydimethylsiloxane (PDMS) membranes have been accepted as the most commonly used in vitro skin mimic because of their homogeneity, uniformity and skin-analogous rate-limiting permeation properties. This thesis investigates the effects of ionisation and surfactants on the permeation of pharmaceutical compounds of varied physicochemical properties through PDMS membranes using a flow-through diffusion cell system. Data suggests that drug permeation had a dependency on the extent of its ionisation, with the permeation being more favourable for the more unionised form of a drug. All of the surfactants studied were found to reduce the permeation of the drugs, with an inverse relationship being observed between the surfactant concentration and the amount of drug permeated. DSC (differential scanning calorimetry), SEM (scanning electron microscopy), FTIR (Fourier transform infrared) and NMR (nuclear magnetic resonance) spectroscopy were employed to study the interactions between the membrane and the surfactants. Results indicated that the permeation effects of the surfactants are a consequence of the interactions between the drugs and surfactant micelles, and/or the membrane and the surfactants. Air plasma treatment was used to modify the PDMS surfaces to become hydrophilic, which was confirmed by water contact angle (WCA) and SEM-EDX analysis. The permeation data for the modified membranes revealed that the plasma-induced hydrophilicity significantly reduced the fluxes of the hydrophobic compounds, while not affecting that of the hydrophilic drug. Aging studies of the plasma-treated membranes showed that the hydrophilic surfaces were maintained even after 8 weeks under airtight storage conditions. In summary, ionisation and surfactant effects on drug permeation across PDMS were thoroughly investigated, and plasma treatment was found to be a stable, economic and convenient method of modifying PDMS to offer skin-like slower drug permeation i.e. to produce a potential in vitro skin mimic.

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Ramsey, E. D. "Studies of pharmaceutical products and peptides by chromatographic and spectroscopic techniques." Thesis, Cardiff Metropolitan University, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.482906.

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Biasi, Verner de. "The application of low dispersion liquid chromatography in the pharmaceutical industry." Thesis, Open University, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.259485.

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Mansa, Rachel Fran. "Roll compaction of pharmaceutical excipients and prediction using intelligent software." Thesis, University of Birmingham, 2007. http://etheses.bham.ac.uk//id/eprint/5406/.

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Roll compaction is a dry granulation method. In the pharmaceutical industry it assists in binding tablet ingredients together to form a larger mass. This is conducted to ease subsequent processing, decrease dust, improve flowability, improve material distribution, more suitable for moisture and heat sensitive materials than wet granulation methods, minimises operating space and suited for a continuous manufacturing set-up. In pharmaceutical roll compaction various types of powder material mixtures are compacted into ribbon that are subsequently milled and tableted. The aim of this research is to investigate the use of intelligent software (FormRules and INForm software) for predicting the effects of the roll compaction process and formulation characteristics on final ribbon quality. Firstly, the tablet formulations were characterised in terms of their particle size distribution, densities, compressibility, compactibility, effective angle of friction and angle of wall friction. These tablet formulations were then roll compacted. The tablet formulation characteristics and roll compaction results formed 64 datasets, which were then used in FormRules and INForm software training. FormRules software highlighted the key input variables (i.e. tablet formulations, characteristics and roll compaction process parameters). Next these key input variables were used as input variables in the model development training of INForm. The INForm software produced models which were successful in predicting experimental results. The predicted nip angle values of the INForm models were found to be within 5%, which was more accurate to those derived from Johanson’s model prediction. The Johanson’s model was not successful in predicting nip angle above the roll speed of 1 rpm due to air entrainment. It also over-predicted the experimental nip angle of DCPA and MCC by 200%, while the approximation using Johanson’s pressure profile under-predicted the experimental nip angle of DCPA by 5-20% and MCC by 20%.

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Lee, Kai Teck. "Continuous granulation of pharmaceutical powder using a twin screw granulator." Thesis, University of Birmingham, 2013. http://etheses.bham.ac.uk//id/eprint/4002/.

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Twin screw extruder (TSE) has been studied extensively as a granulator because it allows continuous processing. Initial work was carried out by comparing the TSE with conventional granulator shows that the mechanism of TSE granulation is different from conventional granulation with the absence of the consolidation stage. PEPT was also utilised and it reveals that the flow stream of the material is not only due to the conveying capacity but also the granulator fill, in particularly for the 90o mixing zone which is believed to be a dispersion type of mechanism driven by the granulator fill gradient. Residence time distribution was measured and simulated by fitting the experimental data using a continuous stirred tank reactors model. The model describes the experimental curves reasonably well when a plug flow fraction was considered. Generally the mean residence time (MRT) of the system is proportional to the mixing zone angle and is inversely proportional to the screw speeds and flowrate. A study using the variance reduction ratio demonstrates that the TSE granulator used in the present study is able to remove the feed instability given that the ratio of the frequency of the input stream fluctuation to the MRT is high.

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LlinaÌ€s, MartiÌ Antonio J. "Chemical reactivity of penicillins and cephalosporins." Thesis, University of Huddersfield, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.273731.

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Foguth, Lucas Charles. "Integration of quality-by-design into control systems design for continuous pharmaceutical manufacturing." Thesis, Massachusetts Institute of Technology, 2016. http://hdl.handle.net/1721.1/104204.

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Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemical Engineering, 2016.
Cataloged from PDF version of thesis.
Includes bibliographical references (pages 121-126).
In the pharmaceutical industry there has recently been much interest in design spaces: sets of critical process parameters (CPPs) which guarantee that critical quality attributes (CQAs) of a manufacturing process are within specifications. For continuous pharmaceutical processes, design spaces are usually calculated by assuming steady state operation and approximating the mapping between CPPs and CQAs using a Taylor series. The full design space can then be calculated using a plantwide approach or a unit-by-unit approach. Common inner approximations of the design space (e.g. hyper-rectangles) can result in significant conservatism, especially when a unit-by-unit approach is employed. Because control loops tend to have a linearizing effect on processes, design spaces for closed-loop processes can often be calculated using low-order Taylor series approximations, resulting in simpler expressions for the full design space (e.g. polytopes). Control loops also tend to enlarge design spaces, sometimes by more than an order of magnitude. Unfortunately, disturbances, noise, and uncertainties will prevent real processes from ever reaching "steady state". Therefore, design spaces calculated at steady state cannot be used to guarantee quality specifications. In fact, because design spaces fail to take into account any process dynamics, constraining a controller to work within a design space may result in failure to meet quality specifications, significant degradation of controller performance, and input jitter. As a substitute for design space, robust model predictive control (RMPC) is a promising technology for dynamically guaranteeing constraint satisfaction on process outputs. Although many RMPC algorithms have been proposed in the literature, the computational cost of these algorithms tends to be a strong function of the state vector size. This is problematic for continuous pharmaceutical processes, which are typically high- or infinite-dimensional. However, input-output models (e.g. finite step response models) can integrated with traditional RMPC strategies to robustly control high-dimensional systems. Although RMPC can be used to counteract the presence of disturbances, uncertainty, and measurement noise, faults also present a threat to quality constraint satisfaction of continuous pharmaceutical processes. Active fault diagnosis of hybrid systems is particularly difficult due to the explosion of mode combinations with prediction horizon. Fortunately, the set of input sequences which do not guarantee diagnosis can be outer bounded offline as a function of a parameterized initial condition set. This enables an algorithm for guaranteed active fault diagnosis of hybrid systems which can be implemented quickly online.
by Lucas Charles Foguth.
Ph. D.

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35

Parshad, Henrik. "Design of poorly soluble drug salts : pharmaceutical chemical characterization of organic salts /." [Cph.] : Department of Pharmaceutics, The Danish University of Pharmaceutical Sciences, 2003. http://www.dfh.dk/phd/defences/henrikparshad.htm.

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Gendrin, Christelle Hirsch Ernest. "Chemical imaging and chemometrics for the analysis of pharmaceutical solid dosage forms." Strasbourg : Université de Strasbourg, 2009. http://eprints-scd-ulp.u-strasbg.fr:8080/1031/01/GENDRIN_Christelle_2008.pdf.

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Obradovic, Jelena. "Development of terahertz techniques for application in the chemical and pharmaceutical industries." Thesis, University of Cambridge, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.613263.

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Gendrin, Christelle. "Chemical imaging and chemometrics for the analysis of pharmaceutical solid dosage forms." Université Louis Pasteur (Strasbourg) (1971-2008), 2008. https://publication-theses.unistra.fr/public/theses_doctorat/2008/GENDRIN_Christelle_2008.pdf.

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Des systèmes d'imagerie hyperspectrale ont été mis sur le marché pour l'analyse chimique microscopique et macroscopique. Constitués d'un détecteur plan présentant une matrice de pixels, ou d'un détecteur point lié à une plateforme mobile, ils peuvent acquérir des spectres localisés spatialement [. . . ]. Les données générées ont donc deux dimensions spatiales et une dimension spectrale, formant ainsi un cube de données. Elles permettent à la fois l'identification des constituants des échantillons et la visualisation de leur distribution spatiale. L'industrie pharmaceutique s'est vivement intéressée à ce nouveau mode d'analyse chimique. En effet, l'homogénéité des différents constituants est essentielle pour la qualité globale des comprimés pharmaceutiques. Par exemple, un mélange non homogène peut engendrer des problèmes au niveau de la production des comprimés comme une adhérence de la poudre sur les poinçons de la presse, ou produire des comprimés n'ayant pas la quantité nominale en Principe Actif (PA), la molécule soignant la maladie, ou encore amener des différences de dissolution et donc influencer l'efficacité du principe actif. De plus, depuis 2002, l'administration américaine imposant les normes de qualité sur les produits pharmaceutiques et alimentaires, La Food and Drug Administration (FDA), promeut la mise en place d'outils de suivi de la production et de contrôle qualité tout au long de la chaîne de fabrication, lançant ainsi l'initiative PAT (Process Analytical Technology). Afin d'améliorer la qualité de leur production et de diminuer le nombre de lots rejetés, les industries pharmaceutiques suivent aujourd'hui ces instructions et tendent à implémenter des nouveaux outils de contrôle. Pour ces raisons, les systèmes d'imagerie chimique non destructifs ont toute leur place dans l'industrie pharmaceutique. . . [etc]
By combining both spectral and spatial information Near Infrared Chemical Imaging (NIR-CI) allows the identification of the chemical species and their localization. Since the distribution of chemical species influences greatly the quality attributes of the medicine this kind of instrumentation has naturally shown to be very useful for the development of pharmaceutical products. However, each analysis generates thousands of spatially resolved spectra which need to be processed for objective comparison of the data. In the present work, the extraction of distribution maps and their characterization is firstly addressed. In that case the samples' composition is fully known and specific wavelengths or the full reference spectra are used to localize the chemical species. Histogram analysis is performed to assess the homogeneity of the first intermediates revealing a batch with greater inhomogeneity. In the second intermediates, a difference in the particle sizes of two batches is enhanced using a segmentation scheme based on Otsu thresholding and watershed refinement. The usefulness of NIR-CI and image processing to study and compare the quality of intermediates is demonstrated. In a second part, the simultaneous extraction of spectra and distribution maps without a priori information is proven. The accuracy of NMF, BPSS, MCRALS and PMF algorithms are compared. The latter proves to extract both spectral profile and concentration with the best accuracy especially when rotational tools are used to investigate the space of feasible solutions. The last chapter deals with the quantification of API in binary mixtures and pharmaceutical tablets. The quantification without a priori reveals to be quite challenging. With homogeneous sample, the multivariate curve resolution algorithms fail to recover the pure spectra. A segmentation scheme is appropriate only in specific cases if the chemical species particles are larger than the spatial resolution of the device. If a full range of tablets with known concentration is provided, PLS algorithm gives the most accurate quantification results. However, it is demonstrated that with the only knowledge of reference spectra, PLS-DA provides an estimation of the concentration which allows semi-quantitative analysis of samples when the construction of a full range is not possible for instance during the analysis of development samples

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39

Flagg, Melissa L. "Bioprospecting, chemical investigations and drug discovery from Chilean plants." Diss., The University of Arizona, 2000. http://hdl.handle.net/10150/284167.

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This dissertation, completed as part of an International Cooperative Biodiversity Group (ICBG) Program, encompasses the field collection, taxonomic determination, bioassay-guided isolation, and chemical characterization of three plants native to Chile, each of which was collected using a distinct collection approach. Chuquiraga ulicina ssp. ulicina , collected by the ecological or environmental strategy, yielded ten compounds including four novel taraxastane-type triterpenoids, 3β-acetoxy-6β-hydroxytaraxasta-20-ene (1), 6β-hydroxytaraxast-20-en-3-one (2), 6β-hydroxytaraxasta-20-ene 3β-palmitate (3), and 3β, 6β-dihydroxytaraxasta-20-ene (4), together with the known triterpenoids lupeol (5), lupenyl acetate (6), lupenone (7), friedelinol ( 8), 3β-acetoxy-30-nor-lupan-20-one (9), and 30-norlupan-3β-ol-20-one (10). Lupeol (5) was the only compound to show antitubercular activity. Sphacele salviae, collected by the ethnobotanical or ethnomedical approach, allowed the isolation of three known compounds, including the two abietane diterpenoids carnosol ( 11) and rosmadial (12), as well as one pentacyclic triterpenoid, ursolic acid (13). Greigia sphacelata, collected according to the random approach, afforded nine compounds. These include the two novel flavanones 5,7,3'-trihydroxy-6,4' ,5'-trimethoxy flavanone (14) and 5,3'-dihydroxy-6,7,4',5 '-tetramethoxy flavanone (15), as well as four known phenylpropanoids, 1,3-O-di-trans-p-coumaroylglycerol (16), 1-O-trans-cournaroylglycerol (17 ), 1-(ω-feruloyldocosanoyl)glycerol and 1-(ω-feruloyltetracosanoyl)glycerol (18), and trans-ferulic acid 22-hydroxy docosanoic acid ester (19), and three known pentacyclic triterpenoids, arborinone (20), arborinol (21), and isoarborinol (22).

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40

Ferguson, Ronald Dale 1966. "Design, synthesis and biological screening of combinatorial chemical libraries." Thesis, The University of Arizona, 1996. http://hdl.handle.net/10150/278584.

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Although combinatorial libraries owe their inception to applications in peptide and bacteriophage libraries, the breadth of current applications include solution phase chemical reaction optimization, material science investigation, natural products modifications, and agricultural research. As a conceptual application, combinatorial library techniques can enhance a researcher's ability to transcend beyond the examination of one or several compounds to that of thousands or millions of these species simultaneously. The work described here, limited to scaffolded combinatorial chemical libraries, focuses primarily on the design and synthesis of these systems and how they have been analyzed against biological targets. Of the three scaffolded libraries, two were developed from aromatic templates (3,5-diaminobenzoic acid and 1,2,4-benzenetricarboxylic acid) while the last was built upon the cyclohexyl, Kemp's triacid platform. Although these libraries did not provide compounds with high affinity for the receptors investigated, they served to improve the understanding of combinatorial chemistry as a practice.

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41

Schofield, C. "Chemical and enzymatic synthesis of beta-lactam antibiotics." Thesis, University of Oxford, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.355775.

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42

Carthew, David Leonard. "Physico-chemical properties of poloxamer surfactants related to adsorption." Thesis, University College London (University of London), 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.243418.

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43

Coromili, Vaia. "Amyloglucosidase immobilized on the surface of polyterephthalamide microcapsules containing multienzyme system with cofactor regeneration for the conversion of urea or ammonia to L-amino acids." Thesis, McGill University, 1991. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=60003.

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Multienzyme systems with cofactor recycling have been immobilized within artificial cells (AC) to carry out certain metabolic functions in living cells. In liver failure there is an increase in systemic ammonia levels and a decrease in the ratio of branched chain (BCAA) to aromatic amino acids (AAA). The multienzyme system consisting of: urease, leucine dehydrogenase (LDH), glucose dehydrogenase (GDH) and immobilized coenzyme (dextran-NAD$ sp+$) is encapsulated in polyterephthalamide microcapsules with amyloglucosidase (AG) adsorbed on the surface: AG-MIC (1% albumin (BSA), Urease, LDH, GDH, dextran-NAD$ sp+$). Such AC may be administered orally where ammonia and urea would be removed while L-leucine, L-valine, L-isoleucine (BCAA) produced from the incorporation of ammonia to the corresponding $ alpha$-keto-acids would diffuse freely across the intestinal tract. Results show that 1 ml of 10% albumin filled AC with a mean diameter of 86.9 $ mu$m can adsorb a maximum of 94.87 mg of AG at PH = 8.0 and T = 37$ sp circ$C.

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44

Kuzak, Stephen G. (Stephen Gerard). "Foaming and the production of the antibiotic bacillomycin L." Thesis, McGill University, 1991. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=60637.

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An examination was made of the effect of a variety of process parameters on the foam capacity of a fermentation broth. The foaming was found to be directly related to the concentration of bacillomycin L, a surface active antibiotic produced by a strain of Bacillus subtilis. Changing the pH was found to have no direct effect on foam capacity. Lowering the incubation temperature reduced foaming but only by decreasing the production of bacillomycin L. Likewise, reductions in the concentration of glutamic acid, the nitrogen source in the medium, resulted in corresponding reductions in foam capacity, bacillomycin concentration and biomass concentration. When glutamic acid was replaced with sodium nitrate, the effects were similar. However, when glutamic acid was replaced with ammonium chloride, cell growth was poor and bacillomycin production was very low. When the pH was controlled by increasing the amount of phosphate in the medium, growth returned to normal while bacillomycin concentration and foam capacity remained relatively low. When the phosphate was replaced with Tris buffer, both bacillomycin production and foam capacity increased to normal levels, indicating that the production of bacillomycin is inhibited by the presence of inorganic phosphates. Finally, when the overall electrolyte concentration of the Tris-buffered medium was increased by 3-4 times, bacillomycin production was high but much of the foaming was suppressed.

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45

Ehteshami, Gholam Reza 1951. "Synthesis and characterization of bioaffinity interactive heterobifunctional polyethylene glycols." Diss., The University of Arizona, 1996. http://hdl.handle.net/10150/282210.

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Novel methods for synthesis of monoprotected homobifunctional polyethylene glycols and subsequent synthesis and application of heterobifunctional derivatives in protein immobilization and separation is described. In addition, modification of proteins with PEG and properties of the conjugates are presented. Heterobifunctional PEG derivatives having a chelate at one end and at the other one specific ligands for proteins have been synthesized. Metal binding constants and kinetic parameters of these bifunctional chelate polymers were found in excellent correlation with the binding affinities shown by corresponding unconjugated groups. These heterobifunctional PEG derivatives were used to characterize the partitioning behavior of several proteins in Affinity Two-Phase Partitioning, ATPP, at different conditions. Both sides of these bioaffinity chelating polymers were found to be effective in the partitioning of these model proteins. These modified heterobifunctional affinity chelating polymers were also adsorbed in aqueous media to different chelating adsorbents used in IMAC separation. In this scheme an IMA-adsorbent could be transformed to a more selective affinity separation mode, by adding an affinity-chelating ligand. The attached ligand could be removed by weakening the metal interactions between the two chelates in the system which allow the column to operate again in the original IMAC mode, if desired. The amount of these bioligands bound to the columns were a function of the type of the IMA-adsorbents, pH, salts and the metal immobilized on the gels. Trypsin and avidin were bound on columns loaded with a PAB-PEG-chelate and a biotin-PEG-chelate respectively. As a typical example, bound trypsin was eluted from the columns with the trypsin inhibitor, benzamidine, acting as a competitive ligand. The bioligands were eluted reversibly from the IMA-adsorbents, using free IDA as a competitive ligand, using low pH buffers or EDTA. PEG derivatives of 5000 daltons, were chemically fixed to non essential groups on trypsin through amidation with amino groups using two different methods. Kinetic studies were performed upon modification to determine the activity and stability of the modified biomolecule under these conditions. In both cases the modified enzyme adduct, retained their original biological activities and showed substantial changes in properties.

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46

Sheng, Shijie. "Applications of Molecular Theory in Solvation of Pharmaceutical Solutes, Ions and Amine-Grafted Silica Gel." Thesis, University of California, Riverside, 2018. http://pqdtopen.proquest.com/#viewpdf?dispub=10684967.

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Solvation and solvent effects play an important role in diverse chemical processes ranging from reaction kinetics to molecular recognition, solubility, solvato-chromism and phase separations. Despite enormous activities in this field, quantitative solvation calculations remain an enormous intellectual challenge.

My thesis is focused on development and application of molecular density functional theory (MDFT) and molecular dynamics (MD) simulation to predicting solvation properties. Accomplishments include 1) improved the average unsigned error of MDFT predictions for the room-temperature solvation free energies (SFE) of 504 pharmaceutical molecules in water from 1.04 kcal/mol to 0.66 kcal/mol; 2) established a more reliable numerical procedure to calculate the direct correlation functions (DCF) of solvent from MD simulations; 3) extended MDFT prediction of SFE to different temperatures and calibrated the theoretical results with experimental data for the hydration free energies of 5 nitrotolunenes and a library of 197 solutes at 277 K, 298 K and 313 K. In addition, I investigated the 3-dimensional (3D) solvation structure of amine-grafted silica gel in liquid water by applying a spherical harmonics expansion method to the MD trajectories. The simulation results provide evidence on the strong influence of the silica surface on hydration structure, which is often ignored in the theoretical analysis of surface reactions. Furthermore, I developed a hybrid method for predicting the SFE of spherical ions by combining MDFT with MD simulations. The numerical analysis justifies the universality of the bridge functional that can be reasonably approximated by the modified fundamental measure theory (MFMT) for hard-sphere systems.

Results from this thesis demonstrate that the DCFs are important in application of MDFT to SFE predictions. Based DCF from on integral-equation methods, MDFT can also capture the temperature effect on SFE in good agreement with experiment. In addition, the hybrid MDFT-MD method provides accurate predictions of hydration free energies for charged solutes and the numerical analysis sheds light on future theoretical development. The efficient sampling method for generating 3D density profiles from MD may open up opportunities for application of MDFT to more complex systems, for example, protein solvation and enzyme kinetics. By studying the solvation structure of amine-grafted silica shell, I found that the silica surface affects not only the distribution of surrounding water but also the hydrogen-bonding network. This surface effect is long-ranged and can be reduced with longer grafted amine chains.

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47

Coffey, Shonna (Shonna Marie). "Achieving business and operational excellence in the pharmaceutical industry." Thesis, Massachusetts Institute of Technology, 2008. http://hdl.handle.net/1721.1/43838.

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Thesis (M.B.A.)--Massachusetts Institute of Technology, Sloan School of Management; and, (S.M.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering; in conjunction with the Leaders for Manufacturing Program at MIT, 2008.
Includes bibliographical references (p. 111-114).
Historically the pharmaceutical industry has been highly profitable. However, the increasing regulatory requirements, bargaining power of buyers, and drug failures together with the threat of biosimilars and decreasing R&D productivity are creating challenges for research driven pharmaceutical companies. With future revenue growth uncertain, pharmaceutical companies must focus on cost reduction to sustain the profit margins needed to support research and development of new medicines. The lean methodology first developed by Toyota is recommended as a way to achieve operational success. A deep analysis of the current state of the pharmaceutical industry and the operational inefficiencies inherent in regulated drug production is provided. The renewed importance of operations within the pharmaceutical business model is explored through a case study of the biotechnology segment's leader, Amgen. Specifically, the design and initial rollout of the Amgen Process Excellence (APEX) initiative is studied. The APEX methodology is a six step process based on lean and six-sigma principles to guide operational improvement activities at Amgen. During the author's internship at the Rhode Island site the rollout of the APEX movement included a current state analysis of the site's financial and operational performance. As a result of this analysis, a prioritized list of improvement ideas was generated and incorporated into a future state vision for the site. Implementation of these improvement ideas is estimated to result in a reduction in cycle time by 55%, lower inventory levels, and the elimination of millions of dollars in waste. The following major conclusions were developed as a result of this work.
(cont.) First, substantial improvement opportunities exist within current pharmaceutical manufacturing. Second, pharmaceutical companies must build operational efficiencies into manufacturing process design. Lastly, operational excellence cannot simply be attained through the implementation of an improvement toolkit.
by Shonna Coffey.
S.M.
M.B.A.

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48

Satara, Chetna Hiren. "Physico-chemical studies on liecithin-based oil-in-water microemulsions." Thesis, King's College London (University of London), 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.299875.

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49

Makein, Lisa Jane. "Correlation of Near-infrared chemical imaging of pharmaceutical dosage forms with their dissolution performance." Thesis, University College London (University of London), 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.498097.

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50

Guedes, Ana Lucia Malheiros. "Environmental practices of transnational corporations in Brazil : cases in the chemical and pharmaceutical sectors." Thesis, London School of Economics and Political Science (University of London), 1998. http://etheses.lse.ac.uk/1508/.

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Following the case study research strategy, this thesis has investigated the implementation of corporate environmental policies in subsidiaries of transnational corporations in Brazil. More specifically, it investigated six subsidiaries from three countries of origin - the United Kingdom, the United States and Germany - operating in the chemical and pharmaceutical sectors. This comparative study has resulted in a theoretical framework to explain transnational corporations' environmental practices. This framework follows an interdisciplinary approach, consisting of four levels. First, at the international level, an overview of the constraints regarding transnational corporations and environmental issues is addressed. The second level is represented by the environmental regulatory policies in the home and host countries. The third level accessed the influences from the industry's structure (in both international and Brazilian contexts). Finally, the fourth level is centred on the companies, which specifically discusses the home-host dilemma in the management of transnational corporations. The most important conclusion is that the main source of pressure over subsidiaries' practices is the environmental regulation of the host country. Nevertheless, there are cases of non-compliance and cases of overcompliance regarding Brazilian environmental legislation. However, these contradictory results are explained by the headquarters-subsidiary relationship. That is, poor environmental performance was explained by lack of control from the headquarters. Otherwise, good performance was explained by tight control from headquarters over subsidiaries' practices in Brazil. Additionally, there is indication that regulation is the main driving force in the home countries. However, attempts at self-regulation are in progress in the chemical industry in order to balance these external pressures for environmental improvements. Finally, there is evidence that the nationality of the selected companies is a relevant aspect of their environmental policies and practices. This is mainly because the legal requirements and management approach of the home countries are incorporated into their environmental management.

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Dissertations / Theses on the topic 'Chemical pharmaceutical'

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