Thesis (Ph. D.)--University of Texas at Austin, 2005. / Supervisor: Gary Rochelle. Vita. Includes bibliographical references.

No description available.

Contaminants in aqueous environments exist in phases that are sorbed to suspended or colloidal material and that are dissolved in solution. Polymer flocculants can be used to remove suspended or colloidal material along with sorbed contaminants, but they remove little of the dissolved contaminants. In the study presented here, development of polymers to sorb contaminants from aqueous solution during the flocculation process was investigated. Atrazine and phosphate (H₂PO₄ ̄) were chosen as test contaminants. For a given test contaminant, multiple copies of a functional group that interacted with that contaminant were inserted into the polymer backbone of a polyacrylamide flocculant. The functional groups inserted into the polymer structure acted as a trap for the dissolved contaminant. The traps were a cyclic secondary amine that interacted with atrazine, and a thiourea that interacted with phosphate. Modified flocculants with different configurations and densities of trapping groups were made and evaluated for removal of the test contaminants from aqueous suspensions. The suspensions consisted of bentonite or kaolinite in water with a known concentration of a test contaminant. The atrazine source was labeled with ¹⁴C and concentrations were measured using a scintillation counter. The source of phosphate used was NaH₂PO₄ and ion chromatography was used to measure the aqueous concentrations of phosphate. In general, the modified polymer flocculants containing trapping groups removed significantly more atrazine and phosphate from suspension compared to the control polymer flocculants ([alpha] =0.05). While the amount of modified polymers needed to achieve significant removal of the test contaminant were higher than the Environmental Protection Agency limit for concentration of polyacrylamide flocculants in water, it was possible to enhance the polymers sorbtion and removal of contaminants from solution during the flocculation process.

Thesis (Ph. D.)--University of Texas at Austin, 2000. / Vita. Includes bibliographical references (leaves 258-270). Available also in a digital version from Dissertation Abstracts.

Rigorous CO₂ absorption models were developed for aqueous 4.5 m K+/4.5 m PZ, monoethanolamine (7m - 9m), and piperazine (8m) in Aspen Plus® RateSepTM. The 4.5 m K+/4.5 m PZ model uses the Hilliard thermodynamic representation and kinetics based on work by Chen. The MEA (Phoenix) and PZ (5deMayo) models incorporate new data for partial pressure of CO₂ vs. loading and kinetics from wetted wall column data. They use reduced reaction sets based on the more relevant species present at the expected operating loading. Kinetics were regressed to match reported carbon dioxide flux data using a wetted wall column (WWC). Density and viscosity were satisfactorily regressed to match newly obtained experimental data. The activity coefficient of CO₂ was also regressed to include newly obtained CO₂ solvent solubility data. The models were reconciled and validated using pilot plant data obtained from five campaigns conducted at the Pickle Research Center. Performance was matched within 10% of NTU for most runs. Temperature profiles are adequately represented in all campaigns. The calculated temperature profiles showed the effect of the L/G on the location and magnitude of the temperature bulge. As the L/G is increased the temperature bulge moves from near the top of the column towards the bottom and its magnitude decreases. Performance improvement due to intercooling was validated across the campaigns that evaluated this process option. Absorber intercooling was studied using various solvent rates (Lmin, 1.1 Lmin and 1.2 Lmin). It is most effective at the critical L/G where the temperature bulge without intercooling is in the middle of the column. In this case it will allow for higher absorption by reducing the magnitude of the bulge temperature. The volume of packing to get 90% removal with L/Lmin =1.1 at the critical L/G is reduced by 30% for 8m PZ. For MEA and a solvent flow rate of 1.1 Lmin packing volume is increased with intercooling at constant L/G. This increase is compensated by higher solvent loadings that suggest lower stripping energy requirements. The critical L/G is 4.3 for 8m PZ, 6.9 for 9m MEA and 4.1 for K+/PZ. / text

This thesis seeks to improve the economic viability of carbon capture process by reducing the energy requirement of amine scrubbing technology. High steam requirement for solvent regeneration in this technology can be reduced by improvements in the regeneration process. Solvent models based on experimental results have been created by previous researchers and are available for simulation and process modeling in Aspen Plus®. Standard process modeling specifications are developed and multiple regeneration processes are compared for piperazine (a cyclic diamine) in Chapter 2. The configurations were optimized to identify optimal operating conditions for energy performance. These processes utilize methods of better heat recovery and effective separation and show 2 to 8% improvement in energy requirement as compared to conventional absorber-stripper configuration. The best configuration is the interheated stripper which requires equivalent work of 29.9 kJ/mol CO₂ compared to 32.6 kJ/mol CO₂ for the simple stripper. The Fawkes and Independence solvent models were used for modeling and simulation. A new regeneration configuration called the advanced flash stripper (patent pending) was developed and simulated using the Independence model. Multiple complex levels of the process were simulated and results show more than 10% improvement in energy performance. Multiple cases of operating conditions and process specifications were simulated and the best case requires equivalent work of 29 kJ/mol CO₂. This work also includes modeling and simulation of pilot plant campaigns carried out for demonstration of a piperazine with a 2-stage flash on at 1 tpd CO₂. Reconciliation of data was done in Aspen Plus for solvent model validation. The solvent model predicted results consistent with the measured values. A systematic error of approximately +5% was found in the rich CO₂, that can be attributed to laboratory measurement errors, instrument measurement errors, and standard deviation in solvent model data. Stripper Modeling for CO₂ capture from natural gas combustion was done under a project by TOTAL through the Process Science and Technology Center. Two configurations were simulated for each of three flue gas conditions (corresponding to 3%, 6% and 9% CO₂). Best cases for the three conditions of flue gas require 34.9, 33.1 and 31.6 kJ/mol CO₂. / text

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The investigations detailed in this dissertation have been conducted to address the paucity of pharmacokinetic information, in published literature, pertaining to cyclizine. The areas of investigation have included the selective quantitation of both cyclizine and its demethylated metabolite, norcyclizine in serum and urine, assessment of stability of both compounds in stored biological samples, dosage form analysis, dissolution rate testing of tablets, and bioavailability and pharmacokinetics following administration of an intravenous solution, and tablets to humans. High-performance liquid chromatography (HPLC) was used as the main analytical technique throughout these studies. An original HPLC method employing ultraviolet detection with a limit of quantitation of 5μg/ℓ was developed for the determination of cyclizine in serum and both cyclizine and norcyclizine in urine, Solid-phase extraction using extraction columns packed with reversed-phase C18 material, and followed by a simple phase-separation step proved successful for the accurate and precise isolation of the compounds. The validated method was applied to the analysis of serum and urine samples from a pilot study in which a single volunteer was administered 50mg of cyclizine hydrochloride. Several samples collected during the pilot study revealed the presence of both drug and metabolite in concentrations below the limit of detection. In order to improve the selectivity and sensitivity of the analytical method an HPLC method with electrochemical detection operating in the "oxidative-screen" mode was developed. The solid-phase extraction procedure was modified slightly and the method found to be precise, accurate, selective and highly sensitive with a limit of quantitation of Iμg/g/l for both cyclizine and norcyclizine in both serum and urine. This method was applied to the determination of both compounds after intravenous and oral administration of cyclizine to humans. HPLC with electrochemical detection was used for the analysis of samples collected during dissolution studies on the batch of tablets used for pharmacokinetic studies. In addition, this method was used to assess content uniformity of the tablets and of samples from the batch of intravenous ampoules of cyclizine lactate. Dissolution studies showed that all tablets tested passed the compendial specifications for cyclizine. Content uniformity assessment revealed that within-batch uniformity existed for both the tablets and ampoules and, therefore, variations in pharmacokinetic parameters for the drug would more than likely be as a result of inter- and intra-individual variability within the subject population. Pharmacokinetic information for cyclizine was obtained following administration of an intravenous bolus dose of cyclizine lactate as a solution, oral administration of cyclizine hydrochloride as a single dose of 50mg and as fixed multiple doses of 50mg every 8 hours for five days. Further information was acquired following administration of single doses of 100mg and 150mg cyclizine hydrochloride. Data collected from these studies were evaluated using both compartmental and non-compartmental techniques. Cyclizine was rapidly absorbed following oral administration with mean kₐ = 1.54 hr⁻¹ and was found to have an absolute bioavailability (F) of 0.47. The presence of norcyclizine in serum following oral and not intravenous dosing suggests cyclizine is susceptible to "first-pass" metabolism in either the gut wall or the I iver. Mean ClTOT determined following the intravenous dose was 0.865 ℓ/hr/kg. The mean ClTOT of 0.823 ℓ/hr/kg calculated following oral dosing, using a unique value of F for each subject compared favourahly with that obtained following intravenous dosing. Renal clearance of cyclizine is negligihle indicating that non-renal routes of elimination account for the majority of removal of cyclizine form the body. Cyclizine is extensively distributed and the mean Vz following an intravenous dose was 16.70 ℓ/kg. This value is lower than that calculated from all oral studies from which the mean Vz was determined to be 25.74 ℓ/kg. Cyclizine is eliminated slowly with a mean elimination t½ = 20.11 hours. Cyclizine dose not appear to follow dosedependent kinetics and therefore, inability to predict steady state levels are more than likely due to accumulation as a result of frequent dosing rather than saturation of elimination mechanisms. Modelling of intravenous data to one-compartment (lBCM), two-compartment (2BCM) and threecompartment models indicated that the pharmacokinetics of cyclizine can be adequately described by a 3BCM. The drug is rapidly distributed into a "shallow" peripheral compartment (α = 9.44 hr⁻¹ , and k₂₁ = 2.09 hr⁻¹ ), and slowly distributed to the "deep" peripheral compartment (β = 0.451 hr⁻¹ and k₃₁ = 0.120 hr⁻¹ ). Modelling of all oral data indicated that a 2BCM best described the pharmacokinetics of the drug, however, distribution to the peripheral compartment is not as rapid as to the "shallow" peripheral compartment following the intravenous dose. Mean distribution parameters were α = 0.64 hr⁻¹1 and, k₂₁ = 0.39 hr⁻¹. Mean CITOT following intravenous dosing of 0.70 ℓ/hr/kg was similar to the mean CIToT of 0.73 ℓ/hr/kg determined after oral dosing. The mean distribution volume at steady state determined following intravenous dosing (17.78 ℓ/kg) was lower than that obtained from the oral studies (25.52 ℓ/kg). The mean terminal elimination half-lives calculated for cyclizine following fitting of intravenous and oral data was 25.09 hours. In general, mean pharmacokinetic parameters calculated following titting of data to a 2BCM after oral administration correlate closely with those calculated using non-compartmental techniques. However, the pharmacokinetics following intravenous dosing are better described by a 3BCM and a close correlation between parameters estimated using noncompartmental techniques and compartmental techniques is evident when a 3BCM model is used.

Although Malaria rates are on the decline due to the efforts of the World Health Organization and other organizations dedicated to the eradication of this disease, a relaxed attitude towards the development of new antimalarial entities would be flawed. Due to the emergence of resistance in the parasite, the almost 50% world-wide reduction in malarial death rates that have been produced over the past 15 years are threatening to be lost New drugs are urgently needed and our approach focuses on the re-evaluation and optimization of the historic antimalarial ICI 56,780. Due to its causal prophylactic activity, along with its ability to prevent transmission and potent blood schizonticidal activities, it was revisited with the hopes of first understanding which functionalities were responsible to the compound's activity. Secondly, we wanted to optimize the substituents in the 3, 6 and 7-positions. Finally and most importantly, we wanted to address the cross-resistance problem of the ICI 56,780 scaffold. Initial, analogues showed the importance of the ester in facilitating the convergence of the RI towards 1. Although those analogues lost activity in W2, TM90-C2B, and Pb, they were our first glimpse at this important trend that was later exploited in our 3-halo-6-butyl-7-(2-phenoxyethoxy)quinolin-4(1H)-one and 3-halo-6-butyl-2-methyl-7-(2-phenoxyethoxy)quinolin-4(1H)-ones which showed RI values of < 5 for our best analogues. Although our lead compound 3-bromo-6-butyl-2-methyl7-(2phenoxyethoxy)quinolin-4(1H) one possessed decreased activities as compared to ICI 56,780 at 2.60 nM for W2, 12.2 nM for TM90-C2B and 2.12 nM for Pb, it had 100% inhibition of parasite development on day 6 PE in our scouting assay and 61% inhibition on day 6in our Thompson model, increased from the < 2% value given by the ICI 56,780. Solubility and unfavorable in vivo stability were still major issues for this scaffold. Therefore, a series of piperazinyl 4(1H)-quinolones with greatly enhanced solubility were designed and tested in detailed structure activity relationships and structure property relationship studies. Initial results showed that 7-piperazinyl-4(1H)-quinolones possessed greatly increased solubilities when compared to ICI 56,780 analogues. Primarily, the linker length and the piperazine core was probed. This showed that compounds with a single carbon spacer were most active. Further testing of the 6-position gave methyl 6-methyl-4-oxo-7-((4-phenylpiperazin-1-yl)methyl)-1,4-dihydroquinoline-3-carboxylate with W2 and TM90-C2B values of 0.435 nM and 147 nM respectively. Substitution on the piperazinyl phenyl gave the most active compounds however the RI of >1500 was unacceptable. Because of this, 3-halo substituents were added to these quinolones with promising results. With RIs of < 3, the compounds were promising, however they were not active in vivo. However, methyl 6-methoxy-4-oxo-7-((4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)methyl)-1,4-dihydroquinoline-3-carboxylate and methyl 6-methyl-4-oxo-7-((4-(4-(trifluoromethyl)phenyl)piperazin-1-yl)methyl)-1,4-dihydroquinoline-3-carboxylate both gave cures in our in vivo Thomson model. These studies highlight the potential in using detailed structural activity and structural property studies to re-evaluate and optimize historic antimalarials. These studies have introduced a new generation of soluble 4(1H)-quinolones with high potency against P. falciparum.

Muscarinic receptors are G-protein-coupled receptors that mediate the response to acetylcholine released from parasympathetic nerves. Although five mAChR subtypes (M1-M5) share a high degree of homology, they display different physiological effects including controlling smooth muscle tone to neurotransmitter release in the CNS. Hence these receptor subtypes have been investigated as potential therapeutic targets for agents capable of treating Alzheimer's Disease, Parkinson's Disease, peptic ulcer disease, COPD, urinary incontinence, and muscle spasms. Our interest in the development of subtype selective muscarinic ligands led to previous reports detailing the identification of substituted lactones as lead muscarinic compounds. Later work involved molecular modifications of those leads that included the addition of aromatic groups with a variety of substitution patterns. These efforts led to an increase in receptor affinity and produced a lactone-based muscarinic ligand with an IC50 of 340nM. As a continuation of that work, additional novel ligands were designed based on the general pharmacophoric elements proposed for the lactone-based ligands. In that model, the lactone oxygens serve as H-bond acceptor moieties while different nitrogen containing heterocycles provide the requisite cationic group. These groups may be separated by linker groups of varying sizes. In order to synthesize the lactone-based ligands mentioned above, efficient synthetic routes are required for key precursors. These include but are not limited to: 1. A novel high yield synthesis of the hydroxyethyl-lactone precursor was designed using a carefully controlled Prins reaction. The method readily quenches a cationic intermediate and simultaneously protects hydroxyl groups in a single step. A mechanism for the new route to the precursor is proposed and its use in the preparation of the target compounds is presented 2. Microwave-assisted synthesis of various sterically hindered N-aryl piperazines has been developed allowing quick access to structurally diverse muscarinic ligands These synthesis along with other newly developed routes enabled ready access to 59 novel muscarinic ligands. The ligands were tested in a general muscarinic binding assay. The result was analyzed and SAR study was performed to direct ligand design. As a result of this work, ligand affinity was improved by over 100 folds compare to the lead molecules. Several promising compounds were selected and selectivity tested. / Pharmaceutical Sciences