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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

Development of LC-MS/MS Methods for the Analysis of Chiral and Achiral Pharmaceuticals and Metabolites in Aqueous Environmental Matrices

Barclay, Victoria K.H. January 2012 (has links)
This thesis describes the development of liquid chromatography tandem mass spectrometry (LC-MS/MS) methods for the trace analysis of active pharmaceutical ingredients (APIs) and their metabolites in aqueous environmental matrices. The research was focused on the development of chiral LC-MS/MS methods for the analysis of fluoxetine and metoprolol, as well as their chiral metabolites in environmental water samples. A method was also developed for the achiral compounds, diazepam and nordiazepam. The LC-MS/MS methods were validated by the use of the isotope-labeled compounds. As these isotope-labeled compounds were not found in the wastewater samples, the validation could be assessed at trace level concentrations in the actual matrices in which the analytes were detected. The analytes were extracted from the water samples using solid phase extraction methods. Different types of solid phase extraction sorbents were evaluated. Fluoxetine and norfluoxetine were extracted through the use of a mixed mode polymeric based extraction sorbent. A hydrophilic and lipophilic balanced sorbent was employed for the simultaneous extraction of metoprolol and its metabolites, the base α-hydroxymetoprolol and the acidic metabolite deaminated metoprolol. Moreover, silica based C18 extraction discs were applied for the sample preparation of diazepam and nordiazepam. The chromatographic separations were conducted in reversed phase LC with MS compatible mobile phases. The enantiomers of fluoxetine and norfluoxetine were simultaneously separated using the chiral stationary phase (CSP), α1-acid glycoprotein (AGP). The Chiral AGP column was also applied for the separation of the enantiomers of deaminated metoprolol. For the simultaneous separation of the metoprolol enantiomers and the four stereoisomers of α-hydroxymetoprolol, the cellobiohydrolase (CBH) protein based CSP was used. An octadecyl silica based LC column was applied for the separation of diazepam and nordiazepam. The analytes were detected by the use of tandem quadrupole mass spectrometry operating in selective reactive monitoring mode. High resolution MS, employing a quadrupole time-of-flight (QqTOF) mass analyzer, was utilized for the identification of an unknown compound in wastewater samples. The APIs and their metabolites, as well as their respective enantiomers, were quantified in raw and treated wastewater from Uppsala, Sweden along with surface water from the River Fyris in Uppsala.
2

Dissolving the Rocks : Solubility Enhancement of Active Pharmaceutical Ingredients using Mesoporous Silica

Xia, Xin January 2014 (has links)
Poor aqueous solubility is one of the greatest barriers for new drug candidates to enter toxicology studies, let alone clinical trials. This thesis focuses on contributing to solving this problem, evaluating the oral toxicity of mesoporous silica particles, and enhancing the apparent solubility and bioavailability of active pharmaceutical ingredients in vitro and in vivo using mesoporous silica particles. Toxicological studies in rats showed that two types of mesoporous silica particles given by oral administration were well tolerated without showing clinical signs of toxicity. Solubility enhancement, including in vivo bioavailability and in vitro intracellular activity, has been evaluated for selected drug compounds. Mesoporous silica was shown to effectively increase drug solubility by stabilizing the amorphous state of APIs, such as itraconazole (anti-fungal), dasatinib (anti-cancer), atazanavir (anti-HIV) and PA-824 (anti-tuberculosis). Itraconazole was successfully loaded into a variety of porous silica materials showing a distinct improvement in the dissolution properties in comparison to non-porous silica materials (and the free drug). Microporosity in SBA-15 particles has advantages in stabilizing the supersaturation state of dasatinib. Small pore sizes show better confinement of atazanavir, contributing to a higher dissolution of the drug compound. In the in vivo animal studies, NFM-1 loaded with atazanavir shows a four-fold increase in bioavailability compared to free crystalline atazanavir. PA-824 has a higher dissolution rate and solubility after loading into AMS-6 mesoporous particles. The loaded particles show similar antibacterial activity as the free PA-824. This thesis aims at highlighting some of the important factors enabling the selection of adequate mesoporous structures to enhance the pharmacokinetic profile of poorly water-soluble compounds, and preparing the scientific framework for uncovering the effects of drug confinement within mesopores of varying structural properties. / <p>At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Submitted. Paper 3: Submitted. Paper 5: Submitted.</p>
3

Engineering of Amorphous Active Pharmaceutical Ingredients by Sonoprecipitation and Spray Drying Pre-and Post-Processing Pharmaceutical Characterisation. Pre- and Post-Processing Physicochemical and Micromeritic Characterisation of Active Pharmaceutical Ingredients

Abdalmaula, Hanan A.S. January 2019 (has links)
Amorphous active pharmaceutical ingredients remain in the research focus as an avenue to achieve a better solubility of drugs. Several processing techniques are applied to produce amorphous materials. Main two approaches applied to production of amorphous phases are comminution of crystalline materials in order to break down molecular long-range order of their crystal lattices and amorphous phase precipitation from solutions. This thesis is focused on processing challenges in preparation of amorphous API phases from solutions by spray drying and evaporative antisolvent sonoprecipitation. Budesonide (BUD) and simvastatin (SMV) were used as model poorly soluble APIs. Amorphous phases of relatively low-glass transition (Tg) APIs are physically unstable and crystallise upon storage and/or processing conditions. To tackle this issue, for the first time in this work a selection of polyvinylpyrrolidone vinyl acetate (PVP-VA) co-polymers has been applied to investigate impact of sonoprecipitation processing parameters and a composition of PVP-VA on physicochemical and micromeritic properties of BUD/PVP-VA nanoparticulate composites. Studies confirmed that in solid-state BUD is miscible with PVP-VA polymers. Application of factorial design revealed that processing parameters: polymer type, surfactant concentrations, time and amplitude of sonication impact the entrapment efficiency, drug loading, polydispersity and particle size properties of produced nanoparticles. The largest fraction of polymer to drug in produced nanoparticles has been achieved with PVP VA E-535. As it is known that polymer content in formulation of APIs may slow down its dissolution, novel approach to processing and dissolution enhancement of amorphous composites of SMV produced by spray drying has been applied. Introduction of easily crystallising inorganic salt- sodium chloride into spray drying feed rendered SMV-polyvinyl pyrrolidone (PVP) amorphous microparticles loaded with nanocrystalline NaCl. Addition of NaCl successfully facilitated generation of discrete microparticles post spray drying with low-Tg polymers, which otherwise were not processable as binary mixtures. In addition, NaCl content aided tabletability and dissolution of amorphous API composites with more viscous and high-Tg PVP polymers. Studies confirmed that application of factorial design facilitates robust design of production process of amorphous nanocomposites by sonoprecipitation as well as that introduction of soluble nanocrystalline phase into amorphous binary solid dispersion by spray drying aids its processing and dissolution.
4

X-ray crystallography and its role in understanding physicochemical properties of pharmaceutical cocrystals

Aitipamula, S., Vangala, Venu R. 2017 May 1929 (has links)
Yes / Properties of a matter are intrinsically dependent upon the internal arrangement of molecules in the solid state. Therefore, knowledge of 3-dimensional structure of the matter is prerequisite for structure-property correlations and design of functional materials. Over the past century, X-ray crystallography has evolved as a method of choice for accurate determination of molecular structure at atomic resolution. The structural information obtained from crystallographic analysis paved the way for rapid development in electronic devices, mineralogy, geosciences, materials science, pharmaceuticals, etc. Knowledge of the structural information of active pharmaceutical ingredients (APIs) is prerequisite for rational drug design and synthesis of new chemical entities for development as new medicines. Over the past two decades, X-ray crystallography has played a key role in the design of pharmaceutical cocrystals-crystalline solids containing an API and one or more of pharmaceutically acceptable coformers. These materials have proved promising for fine-tuning several important properties of APIs. This short review highlights the history of crystallography, early breakthroughs, and the role of crystallography in understanding physicochemical properties of pharmaceutical cocrystals. / S. Aitipamula gratefully acknowledges the financial support from the Institute of Chemical and Engineering Sciences of A*STAR (Agency for Science, Technology and Research), Singapore. V. R. Vangala thanks Royal Society of Chemistry for Researcher Mobility Grant (2015/17).
5

Spectroscopic (FT-IR, FT-Raman, and 13C SS-NMR) and quantum chemical investigations to provide structural insights into nitrofurantoin–4-hydroxybenzoic acid cocrystals

Shukla, A., Khan, E., Alsirawan, M.H.D. Bashir, Mandal, R., Tandon, P., Vangala, Venu R. 04 December 2019 (has links)
Yes / Cocrystallization is an attractive approach to improving the physicochemical properties of active pharmaceutical ingredients (APIs), which have great potential in drug development. Accordingly, there is a growing need to understand the physicochemical changes that occur upon co-crystallisation. This work focuses on the combined use of spectroscopy and density functional theory (DFT) calculations to understand the molecular structure, hydrogen bond interactions and physicochemical properties of a pharmaceutical cocrystal. Solid-state NMR (ssNMR) spectroscopy can provide detailed molecular structure information on pharmaceutical cocrystals and complexes. It is non-destructive and usually provides deep structural insights that complement well with vibrational spectroscopy. In this work, a cocrystal of an antibiotic drug, nitrofurantoin (NF), with 4-hydroxybenzoic acid (4HBA) is examined to understand the capability of multiple spectroscopic techniques such as infrared (IR), Raman and solid-state NMR spectroscopies, and to confirm the molecular structure and hydrogen bonding of cocrystal systems. The results of IR and Raman spectroscopy showed that for the cocrystal formation, NF and 4HBA molecules interact through N–H⋯O–H interactions between the imide N–H of nitrofurantoin and the phenolic –OH of 4-hydroxybenzoic acid, and these interactions are also confirmed by natural bond orbital (NBO) and quantum theory of atoms in molecules (QTAIM) analyses. It is critical to understand whether a given cocrystal, upon conceiving a modified crystalline structure compared to that of its API, shows enhanced physical and chemical properties or not. Computationally, it is found that the NF–4HBA cocrystal shows softer (more reactive) behaviour in comparison to NF as its cocrystal, NF–4HBA, has a low band gap in comparison to the API, NF. These results demonstrate that the quantum chemical approach predicts accurately how to relate cocrystal with its physical and chemical properties. / BSR meritorious fellowship scheme. The Newton-Bhabha PhD placement award (2017). The Royal Society Seed Corn Research Grant (2018-19)
6

Polimorfismo da Clorpropamida investigado através de Espectroscopia Vibracional / Polymorphism of Chlorpropamide investigated through of the vibrational spectroscopy

Caetano, Márcia de Windson Costa January 2006 (has links)
CAETANO, Márcia de Windson Costa. Polimorfismo da Clorpropamida investigado através de Espectroscopia Vibracional. 2006. 141 f. Dissertação (Mestrado em Física) - Programa de Pós-Graduação em Física, Departamento de Física, Centro de Ciências, Universidade Federal do Ceará, Fortaleza, 2006. / Submitted by Edvander Pires (edvanderpires@gmail.com) on 2015-05-21T22:22:40Z No. of bitstreams: 1 2006_dis_mwccaetano.pdf: 3508898 bytes, checksum: d30348bd90f71bc8902edd696cad9095 (MD5) / Approved for entry into archive by Edvander Pires(edvanderpires@gmail.com) on 2015-05-22T19:39:13Z (GMT) No. of bitstreams: 1 2006_dis_mwccaetano.pdf: 3508898 bytes, checksum: d30348bd90f71bc8902edd696cad9095 (MD5) / Made available in DSpace on 2015-05-22T19:39:13Z (GMT). No. of bitstreams: 1 2006_dis_mwccaetano.pdf: 3508898 bytes, checksum: d30348bd90f71bc8902edd696cad9095 (MD5) Previous issue date: 2006 / Chlorpropamide (C10H13ClN2O3S, (1-[4-chlorobenzenesulphonyl]-3-propyl urea)) is a drug used to treat type II diabetes (non-dependent of insulin), especially when the diabetes can not be controlled by alimentary regimes. The polymorphism of this drug is widely documented exhibiting at least five crystalline forms. In this work, we present a vibrational study of four of these polymorphs by using Raman, infrared and near-infrared spectroscopies. The objective of this vibrational investigation is to correlate the vibrational modes with the possible crystalline structures, as well as, to evaluate these methods as a tool for identification and quality control of raw materials and formulated products. In order to provide a detailed characterization we also applied thermal analyses and x-ray powder diffraction techniques to identify the crystalline forms. Finally, the assignment of the bands observed in the vibrational spectra in terms of the normal vibrational modes was performed with the help the quantum mechanical calculations based on the density functional theory. These results allow us to investigate the conformational stability of chlorpropamide establishing correlations with the polymorphism of this drug. / A clorpropamida (C10H13ClN2O3S, (1-[4-chlorobenzenesulphonyl]-3-propyl urea)) é uma droga usada para tratar o diabetes tipo II (não dependente da insulina), em particular em pessoas cujo diabetes não pode ser controlada só pelo regime alimentício. O polimorfismo desta droga se encontra amplamente documentado exibindo, pelo menos, cinco diferentes formas cristalinas. Neste trabalho apresentamos um estudo de quatro destes polimorfos através das espectroscopias Raman, infravermelho e infravermelho próximo. O objetivo desta investigação vibracional é estabelecer correlações entre os modos vibracionais e as possíveis estruturas cristalinas, além de avaliar estes métodos como ferramentas para a identificação e controle de qualidade das matérias primas e produtos formulados. No intuito de prover uma caracterização detalhada também empregamos análises térmicas e difração de raios- X para a identificação prévia das formas cristalinas. Finalmente, a classificação das bandas observadas nos espectros vibracionais em termos dos modos normais de vibração da molécula foi realizada com a ajuda de cálculos computacionais baseados na teoria do funcional de densidade. Estes resultados também nos permitiram investigar a estabilidade conformacional da clorpropamida e estabelecer correlações com o polimorfismo da mesma.
7

Analysis Of Intermolecular Interactions In Pharmaceutical Salts And Cocrystals

Dasgupta, Archi 06 1900 (has links) (PDF)
The studies on cocrystals and salts presented in the the chapters clearly bring out the influence of intermolecular interactions as the main evaluators of the cocrystal-salt regime. The observations made in Chapter 2 indicate that in case if the cocrystal formation is through hydrogen bonds the location of the proton decides the nature of the complex in the energy landscape. The observation that the coformer controls the topology of intermolecular space as demonstrated in Chapter 3 provides insights into the importance of directionality rather than strength of intermolecular interactions. Indeed halogen bonding in cocrystals gain importance in this context.
8

Exploring the interaction between functional carbohydrate polymers and small-molecule active compounds

Jingfan Chen (6369032) 30 April 2021 (has links)
<p>Naturally occurring carbohydrates polymers and their functional derivatives play important roles in the research and technology development in the food, nutrition, and pharmaceutical areas. A major property of these polymeric materials is to associate, enable, enhance, and/or deliver small-molecule active compound such as phytochemicals, nutraceuticals, and active pharmaceutical ingredients (APIs). The goal of this project was to synthesize and characterize phytoglycogen-based materials and study their structure-function relationships in association with selected small-molecule active compounds, including resveratrol, a food-related poorly water-soluble phenolic compound, griseofulvin, an insoluble API, and CCVJ (9-(2-carboxy-2-cyanovinyl) julolidine) a molecular rotor used as a structural probe of polymeric materials. </p><p>In this study, phytoglycogen (PG) was derivatives to phytoglycogen octenyl succinate (PG-OS), hydroxypropyl phytoglycogen (HPP), and octenylsuccinate hydroxypropyl phytoglycogen (OHPP). PG, HPP, and OHPP were evaluated for their efficacy in improving the solubility and Caco-2 permeation of resveratrol and griseofulvin, and using CCVJ, PG-OS was evaluated on its performance at oil-water interface in comparison with OSA-starch, acacia gum, and sodium caseinate. The results showed that: 1) PG, HPP, and OHPP substantially improved the soluble amount and Caco-2 monolayer permeation of resveratrol and griseofulvin, and anti-fungal efficacy of griseofulvin in the aqueous system were significantly enhanced; suggesting that the active ingredients were effective solubilized and released to become bioavailable, 2) among all PG-based biopolymers, OHPP showed superior performance in solubilizing resveratrol and griseofulvin, and 3) in the oil-water two-layer model system, PG-OS, OSA-starch, acacia gum, and sodium caseinate all affected the transferring of CCVJ from oil to aqueous phase, and the effect was monitored and interpreted by the emission spectra of molecular rotor; in the emulsion system, the emission peak wavelength of CCVJ was correlated with the amount of biopolymer adsorbed at the interface of emulsion droplets, and the molecular rotor-based method can be used to characterize the interfacial adsorption of biopolymer at the interface in oil-in-water emulsion.</p><p>This study provides information on the interactions between phytoglycogen-based biopolymers and poorly water-soluble active ingredients, and may potentially supports the study of new functional ingredients interaction with phytoglycogen-based biopolymers in aqueous system. Furthermore, this work allowed us to advance the use of molecular rotor as new analytical tool to study the physicochemical properties of biopolymer.</p>
9

Polimorfismo da Clorpropamida investigado atravÃs de Espectroscopia Vibracional / Polymorphism of Chlorpropamide investigated through of the vibrational spectroscopy

MÃrcia de Windson Costa Caetano 14 March 2006 (has links)
Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / A clorpropamida (C10H13ClN2O3S, (1-[4-chlorobenzenesulphonyl]-3-propyl urea)) à uma droga usada para tratar o diabetes tipo II (nÃo dependente da insulina), em particular em pessoas cujo diabetes nÃo pode ser controlada sà pelo regime alimentÃcio. O polimorfismo desta droga se encontra amplamente documentado exibindo, pelo menos, cinco diferentes formas cristalinas. Neste trabalho apresentamos um estudo de quatro destes polimorfos atravÃs das espectroscopias Raman, infravermelho e infravermelho prÃximo. O objetivo desta investigaÃÃo vibracional à estabelecer correlaÃÃes entre os modos vibracionais e as possÃveis estruturas cristalinas, alÃm de avaliar estes mÃtodos como ferramentas para a identificaÃÃo e controle de qualidade das matÃrias primas e produtos formulados. No intuito de prover uma caracterizaÃÃo detalhada tambÃm empregamos anÃlises tÃrmicas e difraÃÃo de raios- X para a identificaÃÃo prÃvia das formas cristalinas. Finalmente, a classificaÃÃo das bandas observadas nos espectros vibracionais em termos dos modos normais de vibraÃÃo da molÃcula foi realizada com a ajuda de cÃlculos computacionais baseados na teoria do funcional de densidade. Estes resultados tambÃm nos permitiram investigar a estabilidade conformacional da clorpropamida e estabelecer correlaÃÃes com o polimorfismo da mesma. / Chlorpropamide (C10H13ClN2O3S, (1-[4-chlorobenzenesulphonyl]-3-propyl urea)) is a drug used to treat type II diabetes (non-dependent of insulin), especially when the diabetes can not be controlled by alimentary regimes. The polymorphism of this drug is widely documented exhibiting at least five crystalline forms. In this work, we present a vibrational study of four of these polymorphs by using Raman, infrared and near-infrared spectroscopies. The objective of this vibrational investigation is to correlate the vibrational modes with the possible crystalline structures, as well as, to evaluate these methods as a tool for identification and quality control of raw materials and formulated products. In order to provide a detailed characterization we also applied thermal analyses and x-ray powder diffraction techniques to identify the crystalline forms. Finally, the assignment of the bands observed in the vibrational spectra in terms of the normal vibrational modes was performed with the help the quantum mechanical calculations based on the density functional theory. These results allow us to investigate the conformational stability of chlorpropamide establishing correlations with the polymorphism of this drug.
10

Extending the Search Space for Novel Physical Forms of Pharmaceuticals and Biomolecules using High-Pressure Techniques

Saouane, Sofiane 30 September 2015 (has links)
No description available.

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