Tesis: "Drugs Chiral drugs"

1

Mifsud, Janet. "Chiral aspects of the disposition and pharmacology of the enantiometers of ethosuximide". Thesis, Queen's University Belfast, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.336672.

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2

Mashile, Tumelo Rameleko. "Enantioanalysis of pharmaceutical compounds". Pretoria : [s.n.], 2005. http://upetd.up.ac.za/thesis/available/etd-02222007-195248.

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3

Layton, Sherry E. "Comparison of various chiral stationary phases for the chromatographic separation of chiral pharmaceuticals /". Electronic version (PDF), 2005. http://dl.uncw.edu/etd/2005/laytons/sherrylayton.pdf.

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4

Kingston, Gillian A. "Chiral chromatography of enantiomeric cardiovascular and other drugs". Thesis, University of Surrey, 1990. http://epubs.surrey.ac.uk/844123/.

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Since the enantiomers of a number of racemic drugs have been found to have different activities or modes of action, enantioselective analysis is becoming more important. A number of different approaches to chromatographic chiral resolutions have been evaluated for their ability to resolve the enantiomers of racemic beta blocking drugs, Three chiral HPLC columns were investigated; a cyclodextrin phase, an (R)-3,5-dinitrabezoylphenylglycine phase and a protein phase. The acid glycoprotein phase successfully resolved atenolol, alprenolol, metoprolol, oxprenolol, propranolol and verapamil with 0.01M phosphate buffer eluents modified with either acetonitrile or isopropanol. The (R)-3,5-dinitrobenzoylphenylglycine phase was used with eluents of Isopropanol in hexane and resolutions of propranolol, oxprenolol, metoprolol, alprenolol and pronethalol were achieved after formation of the 1- or 2-naphthamide derivatives, although no separations were achieved for the underivatised samples. The cyclodextrin phase was also found to be unsuccessful in resolving underivatised samples of propranolol and verapamil. However preliminary results indicate that resolutions are possible after the formation of their trifluoroacetyl derivatives. The cyclodextrin phase was also successfully used to resolve the enantiomers of chlorpheniramine and the geometric isomers of clomiphene. In addition to the chiral HPLC stationary phases, a (+)-10-camphorsulphonic acid mobile phase additive was investigated, although this was found to be completely unsuccessful. Finally the use of a chiral diamide GLC column was investigated. This was not suited to the analysis of beta blockers, even after derivatisation, although derivatised amino acids were well resolved. The use of computer modelling to predict the degree of separation of enantlomers was also investigated for the (R)-3,5-dinitrabenzoyl phenylglycine phase, with the interaction energies between the phase and both isomers of each compound calculated for the most stable conformation. From a comparison with the experimental results, it was shown that this approach to prediction was unsuccessful.

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5

Watt, Alan Paul. "Liquid chromatographic and mass spectrometric methods for the chiral analysis of drugs and drug metabolites". Thesis, University of Hertfordshire, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.421286.

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6

Karlsson, Louise. "P-glycoprotein and chiral antidepressant drugs : Pharmacokinetic, pharmacogenetic and toxicological aspects". Doctoral thesis, Linköpings universitet, Klinisk farmakologi, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-76126.

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The blood-brain barrier (BBB) is formed by the capillary endothelial cells, joined together by tight junctions, with transporter proteins. BBB acts to regulate the brain concentrations of substances including many drugs. Transport across the cells is necessary for a drug to ensure that the drug reaches the site of action and transport proteins such as P-glycoprotein (P-gp; ABCB1) can limit the entrance into various tissues, including the brain. Molecules that are not superimposable on their mirror images and thus exist in two enantiomeric forms (enantiomers) are said to be chiral. A racemic compound is one composed of a 50:50 mixture of two enantiomers, S- and R-enantiomers. Two examples of frequently prescribed racemic drugs are the chiral antidepressants venlafaxine (VEN) and citalopram (CIT). The enantiomers of VEN possess different pharmacodynamic profiles where the R-enantiomer is a potent inhibitor of both serotonin and noradrenaline reuptake (SNRI), while the S-enantiomer is more selective in inhibiting serotonin reuptake (SSRI). The SSRI effect of CIT resides in the S-enantiomer, whereas the R-enantiomer is considered to be therapeutically inactive, or even that it counteracts the effects. The S-enantiomer of CIT is now available as a separate SSRI (escitalopram, EsCIT). VEN and CIT are also among the most commonly found drugs in forensic autopsy cases. Few previous studies have examined a possible enantioselective activity of P-gp. Thus, the general aim of this thesis was to study the enantiomeric distribution of chiral antidepressant drugs, focusing on the role of P-gp in the BBB. For this purpose, a mouse model disrupted of the genes coding for P-gp (abcb1ab (-/-) mice) was used. Brain and serum concentrations of the enantiomers of VEN and CIT, and their major metabolites, were compared to the corresponding wild-type mice (abcb1ab (+/+) mice). The open-field locomotor and rearing activities were examined after chronic VEN administration. In addition to the animal studies, genetic and toxicological aspects of P-gp were studied in a forensic autopsy material, where intoxication cases were compared with cases that were not related to intoxications. The brain to serum concentration ratios for VEN, CIT and EsCIT differed between knockout mice and wild-type mice, with 2-3 fold higher brain concentrations in mice with no expression of P-gp. Hence, all studied drugs, and their major metabolites, were substrates for P-gp. There was no evidence for a stereoselective P-gp mediated transport. The P-gp substrate properties were reflected in the open-field behavior test where the knockout mice displayed increased center activity compared with wild-type mice following chronic VEN exposure. The genotype distribution of ABCB1 SNPs C1236T, G2677T and C3435T in VEN positive cases was significantly (or borderline) different between the intoxication cases and the non-intoxication cases. This difference in genotype distribution was not observed for the CIT positive cases. To conclude, the present work has led to an increased knowledge about how the enantiomers of VEN and CIT are affected by the BBB transporter P-gp. Using an animal model, VEN and CIT have proved to be actively transported out of the brain by P-gp and no difference was observed for the enantiomers with regard to P-gp transport. Further, the ABCB1 genotype distribution was different in intoxication cases compared with non-intoxication cases. Taken together, these findings offer the possibility that the expression of P-gp in humans may be a contributing factor for limited treatment response and increased risk of side-effects following antidepressant drug treatment.

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7

Crabb, Nicholas Clive. "Applications of chiral chromatography to the analysis of drugs and herbicides". Thesis, University of Bradford, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.277117.

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8

Modzabi, Selorm Kwame Busch Kenneth W. Busch Marianna A. "Studies on new approaches of chiral discrimination for chiral analysis by regression modeling of spectral data". Waco, Tex. : Baylor University, 2009. http://hdl.handle.net/2104/5349.

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9

Rimmer, Duncan Adam. "Novel asymmetric microenvironments for separation of enantiomers chiral drugs and natural products". Thesis, Open University, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.254965.

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10

Eriksson, Tommy. "Pharmacokinetics of the enantionmers of thalidomide". Malmö : Lund : Malmö University Hospital ; Lund University, 1997. http://catalog.hathitrust.org/api/volumes/oclc/68945032.html.

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11

Witte, Dirk Theodoor. "High performance liquid chromatography for direct and indirect enantiomeric separations of chiral drugs". [S.l. : [Groningen : s.n.] ; University Library Groningen] [Host], 1992. http://irs.ub.rug.nl/ppn/297969609.

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12

Morrison, Calum M. "Chiral and achiral analysis of benzodiazepine and anti-anginal drugs in forensic toxicology". Thesis, University of Glasgow, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.321443.

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13

Magnus, Nicholas Andrew. "Synthesis of the anthraquinone portion of dynemicin A : Taxanes chiral construction of the A, B and C rings of taxol". Thesis, University of Bristol, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.319045.

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14

Hung, Yi-Feng. "Microbial biotransformation of 2-arylpropionic acids". Thesis, University of Brighton, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.361579.

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15

Marchant, Carol A. "NMR studies of the cyclodextrin complexes of some 2-arylpropionates and their application to chiral analysis". Thesis, University of Bath, 1992. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.303408.

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16

Ying, Weijiang Harmata Michael. "Study of the chemistry of 2,1-benzothiazines and toward the total synthesis of elisapterosin B". Diss., Columbia, Mo. : University of Missouri--Columbia, 2009. http://hdl.handle.net/10355/6968.

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Title from PDF of title page (University of Missouri--Columbia, viewed on March 1, 2010). The entire thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file; a non-technical public abstract appears in the public.pdf file. Dissertation advisor: Dr. Michael Harmata. Vita. Includes bibliographical references.

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17

Harang, Valérie. "Aspects of Optimisation of Separation of Drugs by Chemometrics". Doctoral thesis, Uppsala University, Analytical Pharmaceutical Chemistry, 2003. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-3738.

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Statistical experimental designs have been used for method development and optimisation of separation. Two reversed phase HPLC methods were optimised. Parameters such as the pH, the amount of tetrabutylammonium (TBA; co-ion) and the gradient slope (acetonitrile) were investigated and optimised for separation of erythromycin A and eight related compounds. In the second method, a statistical experimental design was used, where the amounts of acetonitrile and octane sulphonate (OSA; counter ion) and the buffer concentration were studied, and generation of an α-plot with chromatogram simulations optimised the separation of six analytes.

The partial filling technique was used in capillary electrophoresis to introduce the chiral selector Cel7A. The effect of the pH, the ionic strength and the amount of acetonitrile on the separation and the peak shape of R- and S-propranolol were investigated.

Microemulsion electrokinetic chromatography (MEEKC) is a technique similar to micellar electrokinetic chromatography (MEKC), except that the microemulsion has a core of tiny droplets of oil inside the micelles. A large number of factors can be varied when using this technique. A screening design using the amounts of sodium dodecyl sulphate (SDS), Brij 35, 1-butanol and 2-propanol, the buffer concentration and the temperature as factors revealed that the amounts of SDS and 2-propanol were the most important factors for migration time and selectivity manipulation of eight different compounds varying in charge and hydrophobicity. SDS and 2-propanol in the MEEKC method were further investigated in a three-level full factorial design analysing 29 different compounds sorted into five different groups. Different optimisation strategies were evaluated such as generating response surface plots of the selectivity/resolution of the most critical pair of peaks, employing chromatographic functions, simplex optimisation in MODDE and 3D resolution maps in DryLab™.

Molecular descriptors were fitted in a PLS model to retention data from the three-level full factorial design of the MEEKC system. Two different test sets were used to study the predictive ability of the training set. It was concluded that 86 – 89% of the retention data could be predicted correctly for new molecules (80 – 120% of the experimental values) with different settings of SDS and 2-propanol.

Statistical experimental designs and chemometrics are valuable tools for the development and optimisation of analytical methods. The same chemometric strategies can be employed for all types of separation techniques.

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18

Izumi, Kenji. "Synthsis of Chiral Diamines and Aminoalcohols and Development of Practical Synthetic Procedures of Anti-infective Drugs". 京都大学 (Kyoto University), 2009. http://hdl.handle.net/2433/77981.

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19

Noctor, T. A. G. "Chiral separation of drugs and related compounds by high-performance liquid chromatography : Evaluation of enantioselective high-performance liquid chromatographic techniques and their application to drugs, metabolites and related compounds". Thesis, University of Bradford, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.233673.

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20

Svobodová, Dagmar. "Chirální analýza residuí léčiv v odpadních vodách". Master's thesis, Vysoké učení technické v Brně. Fakulta chemická, 2011. http://www.nusl.cz/ntk/nusl-216766.

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The theoretical part shortly describes chirality with focus on chiral pharmaceuticals. The processes of their absorption, distribution, metabolism and elimination in human body are discussed. These points are very important to understand possible fate of chiral drugs in the environment as there is only little data concerning their environmental behaviour. The occurrence and enantioselective toxicity of chiral drugs is also discussed here. One of the chapters describes non-steroidal anti-inflammatory drugs, as they are analyzed in the wastewater in the experimental part, and their occurrence in the environment. The experimental part describes optimization of the enantioselective HPLC method using Chiralpak AD as column for ibuprofen and ketoprofen. Reproducible separation of enantiomers wasn’t achieved for naproxen. Optimized methods were then applied for analysis of samples from municipal wastewater treatment plant in Brno-Modřice.

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21

Gonçalves, Caroline Vieira. "Separação do racemato N-Boc-Rolipram pelo processo cromatografico de leito movel simulado utilizando fase estacionaria quiral tris-(3,5-dimetilfenilcarbamato de celulose) suportada em silica". [s.n.], 2005. http://repositorio.unicamp.br/jspui/handle/REPOSIP/267277.

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Orientador: Cesar Costapinto Santana
Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Engenharia Quimica
Made available in DSpace on 2018-08-04T05:42:04Z (GMT). No. of bitstreams: 1 Goncalves_CarolineVieira_D.pdf: 3183194 bytes, checksum: f2a1cb206fded5b0573c8a68c4578d34 (MD5) Previous issue date: 2005
Resumo: Fases Estacionárias Quirais (FEQs) têm-se mostrado eficientes na resolução de racematos. O Rolipram, (mais ou menos)-4-(3-(ciclopentiloxi)-4-metoxifenil)-2-pirrolidinona, é um antidepressivo que tem apresentado importantes propriedades farmacológicas. A purificação do Rolipram na FEQ tris(3,5-dimetilfenilcarbamato) de celulose adsorvida em sílica através da cromatografia contínua de Leito Móvel Simulado (LSM) foi o objetivo principal deste trabalho. A FEQ foi sintetizada e suas propriedades foram determinadas por análises físicas e químicas. Através de experimentos de adsorção em coluna forma determinados a influência da temperatura sobre o fator de separação ('alfa¿), as isotermas competitivas da adsorção da mistura racêmica e os parâmetros cinéticos e de equilíbrio da separação do N-Boc-Rolipram na FEQ sintetizada. Os experimentos realizados na unidade LSM foram feitos, sob condições diluídas, á temperatura ambiente. O N-Boc-Rolipram foi separado na FEQ sintetizada através do processo cromatográfico contínuo de LMS. As constantes de adsorção de Henry são discutidas e revelam um fator de separação da ordem de 1,20. AS medidas de pureza e excesso enantiomérico das correntes se extrato e refinado forma determinadas. As analises físicas e químicas da FEQ sintetizada revelam boa concordância com os valores teóricos. Efeitos da temperatura sobre o fator de separação mostram que o processo de adsorção é entalpicamente controlado. Ambos os enantiômeros precisam ser realizados par uma melhor compreensão do processo de adsorção. Os parâmetros de equilíbrio e cinética revelam o bom desempenho da FEQ sintetizada na separação dos enantiômeros principalmente o R-Boc-Rolipram
Abstract: Chiral stationary phases (CSPs) have shown efficiency in racemate purification. Rolipram, (mais ou menos)-4-(3-(cyclopentyloxy)-4-methoxyphenyl)- pyrrolidin-2-one, is an antidepressant with significant pharmacological properties. The main objective of this work was Rolipram purification in the Chiral Stationary Phase tris(3,5-dimethylphenylcarbamoyl) cellulose supported on silica by Simulated Moving Bed continuous chromatography. CSP was synthesized and its properties were determined by physical and chemical analysis. Kinetics and equilibrium parameters of the N-Boc-Rolipram, effect of the temperature on the separation factor (a) and competitive isotherms of the racemic mixture were evaluated by adsorption experiments with columns packed with the synthesized CSP. The experiments in the 5MB unit were carried out under diluted conditions at room temperature. The N-Boc-Rolipram racemate was separated on the synthesized CSP by the 5MB continuous chromatographic processoHenry constants are discussed and reveal Selectivity elose to 1,20. Purity and enantiomeric excess of extract and raffinate streams were determined. Chemicals and physicals analyses of the CSP obtained find good agreement with theoretical results. The effects of the temperature on the separation factor show that adsorption process is controlled by the enthalpy. Both enantiomers adsorb similarly on the synthesized CSP, but detailed studies need to be making for a good understanding of the adsorption processoKinetics and equilibrium parameters show good performance of the synthesized CSP to separate the enantiomers, mainly R-Boc-Rolipram racemate
Doutorado
Desenvolvimento de Processos Biotecnologicos
Doutor em Engenharia Química

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22

Tohala, Luma. "Etude par électrophorèse capillaire des propriétés de résolution chirale des oligonucléotides en série ADN". Thesis, Université Grenoble Alpes (ComUE), 2018. http://www.theses.fr/2018GREAV016.

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De nos jours, la stéréochimie des médicaments est devenue un enjeu important aussi bien pour l'industrie pharmaceutique que pour les autorités réglementaires. Il a été démontré que les nucléotides / nucléosides ou les structures en double hélice et tétrade de guanine présentaient certaines propriétés énantio sélectives. Néanmoins, à ce jour, très peu d’études se sont focalisées sur l’utilisation de l’ADN en tant que sélecteur chiral. Grâce à l’utilisation d’une méthode de remplissage partiel, les propriétés de discrimination chirale d'un répertoire d'oligonucléotides (ONs) en série ADN caractérisé par diverses compositions de bases et de structures ont été testées sur une large gamme de mélanges racémiques par électrophorèse capillaire (EC), méthode séparative performante utilisant de faibles volumes d’échantillons. A des concentrations d'ADN sub-millimolaire, il a été montré que tous les ONs en série ADN testés, présentaient des capacités d'énantio discrimination vis-à-vis de plusieurs composés pertinents. Les couples d’énantiomères séparés sont, soit des composés cationiques possédant un groupement phényle, soit des analytes sans charge nette ou avec une charge positive et comportant deux cycles aromatiques. Une étude portant sur les capacités séparatives de plusieurs séquences d'homopolymères poly-dT de longueurs différentes (de 5 à 60-mer) a ensuite été menée sur certains couples d’énantiomères. Les résultats ont montré qu’une longueur minimale de 30 bases, où l'ADN semble adopter une conformation de type pelote, présentait de meilleures propriétés d'énantioséparation qu’une séquence constituée d’un maximum de 10 bases. De plus, la reconnaissance chirale des ONs en série ADN implique principalement des bases d'ADN libres dont la diversité chimique augmente leur capacité d'énantio résolution. Finalement, afin d'étudier la contribution thermodynamique impliquée dans les séparations énantiomériques obtenues par les ONs simples brins testés, des mesures de constantes d’affinité pour les énantiomères du tryptophane ont été réalisées vis-à-vis du Poly-dT30 par trois techniques différentes. Les méthodes utilisées n’ont pas permis de déterminer une différence d’affinité entre les deux énantiomères
Nowadays, drug stereochemistry has become a significant issue for both the pharmaceutical industry and the regulatory authorities. It has been demonstrated that nucleotides/ nucleosides or duplex and G-quadruplex structures showed some enantioselective properties. Nevertheless, to date, the use of DNA as chiral selector has been largely neglected. Using partial filling capillary electrophoresis (CE) method, highly efficient technique with little volume consumption need, the assessment of the enantioselective properties of a repertoire of arbitrarily chosen DNA oligonucleotides (ONs) characterized by diverse base compositions and structural features was studied for a series of various racemates. Under (sub) millimolar DNA concentration conditions, it was shown that all the ONs tested presented enantiodiscrimination properties for interesting organic compounds. The resolved compounds are either cationic carrying one phenyl group or contain two aromatic cycles with no net or one positive charge. Then, sequence prerequisites of ONs for the CE enantioseparation process were studied for a series of homopolymeric sequences (Poly-dT) of different lengths (from 5 to 60-mer) and for the discrimination of various enantiomers. The results showed that the sequence length of 30-mer (or more) of the ONs was better for the enantioseparation properties, where the DNA adopted a coil-like conformation, than ONs with a sequence length ≤ 10-mer. The base-unpaired state constituted also an important factor in the chiral resolution ability of ONs. Moreover, the chemical diversity enhanced the enantioresolution ability of single-stranded ONs. Finally, several attempts have been conducted to study the thermodynamic contribution involved in enantiomeric separation obtained with DNA strands. Binding affinity constants were determined for tryptophan enantiomers towards Poly-dT30 by three different techniques. The used methods did not allow determining a difference of affinity between enantiomers

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23

Han, Jeong Woo. "Density functional theory studies for separation of enantiomers of a chiral species by enantiospecific adsorption on solid surfaces". Diss., Georgia Institute of Technology, 2010. http://hdl.handle.net/1853/34848.

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The distinct response of biological systems to the two enantiomers of a chiral chemical has led to a large market for enantiopure pharmaceuticals and raised fundamental issues about the origin of biological homochirality. It is therefore important to understand the interactions of chiral molecules with chiral environments. Chiral environments associated with solid surfaces could potentially play a useful role in chirally specific chemical processing. There are a variety of routes for creating chiral solid surfaces. Surfaces of materials whose bulk crystal structure is enantiomorphic can be used as one type of chiral solid surfaces. Metal surfaces that are intrinsically chiral due to the presence of kinked surface steps provide another route for creating chiral solid surfaces. Alternatively, we can impart chirality onto surfaces by attaching irreversibly adsorbing chiral organic species on otherwise achiral surfaces. Understanding and ultimately controlling enantiospecific interactions of molecules on this kind of surfaces requires detailed insight into the adsorption geometries and energies of these complex interfaces. To tackle these issues, we performed density functional theory (DFT) calculations that have proved to be a useful tool for quantitative prediction of these effects. Besides our main topic above, we theoretically examine the effects of K atoms as a promoter coadsorbed with small molecules on Mo2C surfaces, a promising catalyst for a range of chemicals applications. Our results in this thesis provide fundamental information about these systems and demonstrate that using DFT for this purpose can be a useful means of identifying the phenomena that control chiral surface chemistry.

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24

Dogra, Jody A. Busch Kenneth W. Busch Marianna A. "Multivariate analyses of near-infrared and UV spectral data". Waco, Tex. : Baylor University, 2009. http://hdl.handle.net/2104/5347.

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25

Yanto, Yanto. "Evaluation of novel enoate reductases as potential biocatalyst for enantiomerically pure compound synthesis". Diss., Georgia Institute of Technology, 2011. http://hdl.handle.net/1853/39576.

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Asymmetric synthesis with biocatalyst has become an increasingly interesting and cost effective manufacturing process in fine chemicals, pharmaceuticals, and agrochemical intermediates. Enoate reductases from the Old Yellow Enzyme family offer high substrate efficiency, region, stereo-, and enantioselectivity in the catalyzed biotransformations. Asymmetric reduction of activated C=C bond is one of the most widely applied synthetic tools for the potential to generate up to two stereogenic centers in one step reaction. The thesis contributed to the development and characterization of the Old Yellow Enzyme family members including NRSal from Salmonella typhimurium, YersER from Yersinia bercoviei, KYE1 from Kluyveromyces lactis, and XenA from Pseudomonas putida. We explored the possible new chemistry, gathered further understanding of enzymes functionality and biochemistry, evaluated parameters such as enzyme stability, productivity, and selectivity, and improved enzyme specificity through computational guided protein engineering method. In overall, the increasing knowledge about this Old Yellow Enzyme family together with recent advances in biotechnology renders the enoate reductases a tool of choice for industrial applications.

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26

Allen, Serena, Stacy D. Brown, Carolyn Reynolds, Erin Hankins y Brooks Pond. "Novel Liquid Chromatography – Mass Spectrometry Method for the Chiral Separation and Quantification of d- and l-threo Methylphenidate in Brain Tissue". Digital Commons @ East Tennessee State University, 2016. https://dc.etsu.edu/etsu-works/5255.

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27

Zu, Chengli. "Enantiomer analysis using electrospray ionization mass spectrometry". Diss., Mississippi State : Mississippi State University, 2007. http://library.msstate.edu/etd/show.asp?etd=etd-04092007-103342.

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28

Castro, João Tiago Duarte Ferreira de. "Benefícios dos estereoisómeros na terapêutica medicamentosa". Master's thesis, [s.n.], 2014. http://hdl.handle.net/10284/4514.

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Projeto de Pós-Graduação/Dissertação apresentado à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de Mestre em Ciências Farmacêuticas
A maioria dos fármacos comercializados atualmente são estereoisómeros, podendo estes apresentar-se na forma de enantiómeros ou diastereómeros. Desde que ocorreu o desastre da talidomida nos anos 60, a indústria química e farmacêutica apercebeu-se da importância do estudo da quiralidade dos fármacos e das suas propriedades estereoquímicas. A análise da correlação entre a quiralidade e as propriedades toxicológicas e farmacológicas dos compostos levou não só à eliminação de efeitos adversos, como também a diversos benefícios terapêuticos. Tem surgido uma tendência para a comercialização de novos fármacos sob a forma de enantiómeros, suplantando os fármacos antigos que eram comercializados na forma de misturas racémicas. Este trabalho expõe alguns benefícios associados aos estereoisómeros presentes em diferentes grupos terapêuticos, através da análise de diferentes misturas racémicas e dos seus enantiómeros ou diastereómeros. The majority of currently marketed drugs are stereoisomers, which can be enantiomers os diastereomers. Since thalidomide’s disaster occurred in the 60’s, the chemical and pharmaceutical industry realized the importance of studying the chirality of drugs and their stereochemical properties. The analysis of the correlation between chirality and the toxicologal and pharmacological properties has let not only to the elimination of adverse effects, but also to different therapeutic benefits. There has been a tendency towards the marketing of new drugs in the form of enantiomers, supplanting the old drugs which were marketed as racemic mixtures. This work exposes some benefits associated with stereoisomers present in different therapeutic groups, through the analysis of different racemic mixtures and their enantiomers or diastereomers.

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29

Dufrasne, François. "Conception et synthèse de nouveaux ligands organiques stéréosélectifs du platine". Doctoral thesis, Universite Libre de Bruxelles, 2002. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/211427.

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Le but du travail de doctorat est la mise au point et l’étude fondamentale de voies de synthèse de diamines sous forme de leurs énantiomères optiquement purs. Ces derniers doivent être testés comme complexes dichloroplatiniques afin de quantifier leur pouvoir antitumoral. Les qualités souhaitées de ces synthèses sont leur application à des molécules de structure variées, les meilleures énantiosélectivité et diastéréosélectivité et les méthodes les plus simples possibles.

Les énantiomères des 1,2-diamino-1-(4-fluorophényl)propanes ainsi que les 1,2-diamino-1-(4-fluorophényl)-3-méthylbutanes ont été obtenus avec des rendements approximatifs globaux de 10 %. Les premières diamines ont été synthétisées par la méthode de Tytgat permettant l’obtention des deux séries d’énantiomères (érythro et thréo) au départ d’un énantiomère aminoalcool intermédiaire érythro. Les diamines érythro sont obtenues par une synthèse de Gabriel stéréospécifique tandis que la série thréo l’est par formation et ouverture par NH3 d’une aziridine, de manière stéréo- et régiosélective. Les butanediamines ont été synthétisées à partir des acides aminés optiquement purs (D- et L-alanine). Les thréos sont obtenues par une réaction de Grignard sur la nitrone dérivée de l’acide aminé N-boc. Les isomères érythro ont été fournis par la formation et l’ouverture régiosélective d’un N,Ndibenzylaziridinium, formé à partir de N,N-dibenzyl-2-amino-1-(4-fluorophényl)-3-méthylbutan-1-ol.

La synthèse des 1,2-diamino-1-(4-fluorophényl)butanes a été entreprise de la même manière mais les aminoalcool intermédiaires n’ont pu être isolés, suite à une réaction secondaire lors de la débenzylation des N,N-dibenzyl-2-amino-1-(4-fluorophényl)butan-1-ol, et ayant conduit à la 2,5-diéthyl-3,6-di(4-luorophényl)pyrazine-[1,2].

L’obtention des 1,2-diamino-1-(2-méthoxyphényl)propanes n’a pu être menée à bien suite aux effets négatifs de l’encombrement stérique et de l’effet mésomère du OMe sur le C-. Ni la voie de Tytgat, ni la synthèse via les diols produits par dihydroxylation asymétrique de Sharpless n’ont abouti.

La pureté énantiomérique a été vérifiée par dérivation chimique au (1R)-(-)-myrténal et enregistrement du spectre RMN 1H des imines obtenues. La réaction est réalisée in situ dans le tube RMN, avec le CDCl3 comme solvant. Cette technique a également permis la confirmation de la configuration absolue par comparaison avec les valeurs déjà obtenues avec les composés non-substitués. La méthode a été vérifiée quant à son étendue et ses limites sur toute une série de composés comprenant des acides-aminés, des amines primaires aliphatiques et des b-aminoalcools. On a pu ainsi prouver que les a-et b-phénylalkylamines sont les seules molécules sur lesquelles la technique est efficace.

Les tests pharmacologiques préliminaires ont été effectués au moyen des complexes dichloroplatiniques de nos produits, sur les cellules cancéreuses mammaires MCF-7. L’introduction du fluor a augmenté l’activité des produits de façon importante, par rapport aux complexes non substitués. L’activité est fortement diastéréosélectives et modérément énantiosélective. Les isomères thréo sont toujours plus actifs que les érythro.

L’examen des résultats a permis de faire l’hypothèse qu’il existe, si pas un transport énantiosélectif, du moins un mécanisme de résistance qui favorise un énantiomère par rapport à l’autre. L’isomère thréo-1S2S est le seul à être cytotoxique à une dose de 1µM.

Doctorat en sciences pharmaceutiques
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30

MONTE, Zenaide Severina do. "Desenvolvimento de um novo método para controle de qualidade do cloridrato de paroxetina e do cloridrato de biperideno por dicroísmo circular". Universidade Federal Rural de Pernambuco, 2012. http://www.tede2.ufrpe.br:8080/tede2/handle/tede2/6382.

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This paper describes the qualitative and quantitative analysis by circular dichroism (CD) of paroxetine hydrochloride and qualitative analysis of biperiden hydrochloride. It was developed the method a simple, rapid, which uses the differential absorption of circularly polarized light right and left environment for the qualification and quantification of raw materials the drugs mentioned above using the technique by circular dichroism. The method developed followed the criteria of rules and recommended by ANVISA and ICH. The paroxetine hydrochloride and biperiden hydrochloride are chiral drug that can be used for the treatment of depression and Parkinson's, respectively. Paroxetine (PRX), a chiral drug, has two stereogenic carbon atoms in its chemical structure. The PRX, was dissolved in ultrapure water concentration 5,47.10-4 molL-1 DC analysis. Their spectrum showed an intense negative Cotton effect in mdeg - 37.4653. The standard curve the solution of reference a correlation coefficient of 0.9907 for the concentration range of the 0,91.10-4/ 5,47.10-4 molL-1. The limits of detection and quantification were 0,197.10-4 and 0,656.10-4 molL-1, respectively. The repeatability and precision intermediate had variance of 1.32. The results showed good accuracy for interval of 95%. The study showed that the recovery of the extraction method of PRX the drug was effective. The method is robust and the samples were stable to temperature variations. The method was selective for quantification of the drug by evaluating the interference of the excipients. Analyses with biperiden, a substance which has four chiral centers, were performed with the secondary standard BPR and the drug by the DC of molar concentrations 3,21.10-3 and 3,21.10-4 respectively. The samples had EC negative as well as the primary standard USP BPR. The spectrum obtained by theoretical calculation showed a positive Cotton effect of the enantiomers of BPR. These results indicate that one of the enantiomers can BPR is in excess or that the substance is pure or impurities which are chiral.
O presente trabalho descreve a análise qualitativa e quantitativa por dicroísmo circular (DC) do cloridrato de paroxetina e a análise qualitativa do cloridrato de biperideno. Foi desenvolvido um método simples, rápida, que faz uso da absorção diferenciada da luz circularmente polarizada a direita e a esqueda para a qualificação e quantificação da matéria-prima e os fármacos citados anteriormente empregando a técnica por dicroísmo circular. O desenvolvimento do método seguiu os critérios das normas vigentes e recomendadas pela ANVISA e ICH. O cloridrato de paroxetina e o cloridrato de biperideno são drogas quirais, que pode ser utilizadas para o tratamento da depressão e de parkinson, respectivamente. A paroxetina (PRX), um fármaco quiral, apresenta dois carbonos estereogênicos em sua estrutura química. A PRX, foi dissolvida em água ultrapura a concentração de 5,47.10-4 molL-1 para análise em DC. O seu espectro apresentou um Efeito Cotton intenso e negativo em -37,4653 mdeg. A curva da solução de referência apresentou um coeficiente de correlação de 0,9907 para o intervalo de concentração de 0,91.10-4 a 5,47.10-4 molL-1. Os limites de detecção e quantificação foram de 0,197.10-4 e de 0,656.10-4 molL-1, respectivamente. A repetitividade e precisão intermediária apresentaram variancia média 1,32. A exatidão apresentou resultados bons para o intervalo de confiança de 95%. O método foi seletivo para quantificação do fármaco avaliando a interferência dos excipientes. As análises com o biperideno, uma substância que tem quatro centros quirais, foram realizadas com o padrão secundário BPR e com o fármaco por DC nas concentrações molares de 3,21.10-3 e de 3,21.10-4 respectivamente. As amostras apresentaram EC negativos, assim como no BPR padrão primário da USP. O espectro obtido por cálculo teórico apresentou um Efeito Cotton positivo para um dos enantiômeros do BPR. Esses resultados indicam que um dos enantiômeros do BPR pode está em excesso ou que a substância está pura ou ainda que existem impurezas quirais.

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31

Thomason, Michael John. "The microbial chiral inversion of drug molecules". Thesis, University of Brighton, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.284046.

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32

Prangle, Anita Susann. "Chiral drug bioanalysis using reduced-dimension separation systems". Thesis, University of Sunderland, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.369863.

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33

Richoux, Jr Gary Michael. "Enantioselective Synthesis of Drug-like Molecules via Axially-Chiral Intermediates". Diss., Virginia Tech, 2016. http://hdl.handle.net/10919/71675.

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The self-regeneration of stereocenters via stereolabile axially-chiral intermediates (SRSvSACI) is a synthetic strategy in which the configuration of a starting material, possessing only a single stereocenter, directs the formation of a chiral axis in an intermediate. The reaction proceeds stereospecifically, although the original stereocenter is destroyed through trigonalization. This is due to the stereochemical information encoded in the chiral axis, which is transformed into the configuration of a stereocenter in the product. In this research, we investigate the generation of axially chiral intermediates arising from both (S)-methyl lactate derivatives and 1,4-benzodiazepin-2,5-dione derivatives. For the deprotonation/alkylation of O-Bn and O-TBS substituted (S)-methyl lactate derivatives containing achiral oxazolidinones, we hypothesized that a twisted amide enolate featuring a chiral C(O-)-N axis could sufficiently impart stereochemical information and control the selectivity of the reaction. Previous work completed by Kobayashi showed in related compounds (E)- vs (Z)-enolate formation could be controlled through the identity of the 2'-oxygen substituent with –Bn affording the (E)-enolate and –TBS affording the (Z)-enolate. We investigated the utilization of achiral oxazolidinone moieties to selectively generate axial chiral intermediates that could then control the facial selectivity of sequential alkylations. Unfortunately, unforeseen synthetic difficulties prevented successful accomplishment of our project goals. We also utilized axially chiral intermediates in the generation of 3,3-disubstituted quinolone-2,4-diones. The target compounds serve as potentially useful drug scaffolds, yet synthetic access to them has remained limited due to the lack of commercial availability of the corresponding enantiopure quaternary substituted amino acids. Prior work in the Carlier group demonstrated the preferential (M)-conformer deprotonation demonstrated by 1,4-benzodiazepin-2,5-diones, and through the installation of an N4-tert-butyloxycarbonyl protecting group, we were able to take advantage of this preferential (M)-conformer deprotonation and generate 3,3-disubstituted quinolone-2,5-diones through an acyl-amino variant of the Chan rearrangement. In general, these reactions were highly enantioselective proceeding with little to no loss of enantiomeric excess. Finally, we collaborated with Professor Bloomquist to test the topical toxicity of selected ring-contracted products against adult Anopheles gambiae, the African vector of malaria.
Ph. D.

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34

Wood, Stephen A. "The analytical and biological enantioselectivity of substituted 2-aminotetralins". Thesis, University of Surrey, 1996. http://epubs.surrey.ac.uk/843160/.

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The enantiomeric discrimination properties of a number of commercial chiral HPLC stationary phases have been examined using a series of 2-aminotetralin analogues. The mobile phase conditions for each column were varied in order to optimise the separation for the largest number of analytes. Factorial experimental design techniques were used to test the empirically derived mobile phase combinations. A primary limitation of factorial design optimisation strategies, the number of experiments required, was overcome by the development of a simultaneous factorial design method utilising the selectivity of mass spectrometric detection. This enabled the optimisation of the separation of the enantiomers of 12 compounds, using Chiral AGP, to be carried out concurrently. None of the columns tried was able to separate the enantiomers of more than half the analytes. The retention mechanism of the Chiral AGP column was shown to be via cation exchange and non-polar interactions. The ability to form a hydrogen bond between the carbon 8 substitution (acceptor) of the analyte and the stationary phase (donor) was found to be a prerequisite for the separation of enantiomers using Chiral AGP and Chiralcel OD. Neither a rule based nor a mathematical model constructed from calculation derived physicochemical and molecular data were sufficient to describe the enantioselectivity of the Chiral AGP stationary phase. A molecular graphics template model was used to demonstrate the importance of the spatial position of the hydrogen acceptor to the enantioselectivity of the column. Two 2-aminoteralins substituted at the carbon 8 position with a keto-pyrrol function were found to be enantioselectively cleared from in-vitro rat liver preparations dependent upon the substitutions attached to the carbon 2 nitrogen. Differences between these closely related structures were shown to be related to the hydroxylation of the parent molecule, probably, although not exclusively, via the cytochrome P450 isozyme CYP2D6. An in-vivo study using an intravenous dose route showed no sign of enantioselectivity or evidence of the major in-vitro metabolite.

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35

Shcherbakova, Elena G. "Implementation of High Throughput Screening Strategies in Optical Sensing for Pharmaceutical Engineering". Bowling Green State University / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=bgsu1510758614142002.

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36

Kuroda, Yukihiro. "Development of microanalytical system for investigation of chiral selective drug bindings of plasma proteins". 京都大学 (Kyoto University), 2002. http://hdl.handle.net/2433/149577.

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37

Carlsson, Björn. "From achiral to chiral analysis of citalopram /". Linköping : Univ, 2003. http://www.ep.liu.se/diss/med/07/93/index.html.

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38

Malm, Mikaela. "Drug Analysis : Bioanalytical Method Development and Validation". Doctoral thesis, Uppsala universitet, Analytisk kemi, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-8547.

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This thesis describes bioanalytical methods for drug determination in biological matrixes, with drugs in focus used against diseases largely affecting low-income countries. Solid-phase extraction is used for sample cleanup, and processed samples are analyzed by liquid chromatography. Developed bioanalytical methods are validated according to international guidelines. Eflornithine (DFMO) is a chiral drug, used for treating human African trypanosomiasis. A bioanalytical method for determination of DFMO enantiomers in plasma is presented. The enantiomers are detected by evaporative light-scattering detection. The method has been applied to determination of D-DFMO and L-DFMO in rats, after intravenous and oral administration of racemic DFMO. It is concluded that DFMO exhibits enantioselective absorption, with the more potent enantiomer L-DFMO being less favored. Sulfadoxine (SD) and sulfamethoxazole (SM) are sulfa-drugs used for malaria and pneumonia respectively. Two methods are described for simultaneous determination of SD and SM in capillary blood sampled on filter paper. The former method allows direct injection of extracts from dried blood spots (DBS), while for the latter method solid-phase extraction is added. Pre-analytical factors contributing to measurement uncertainty is also discussed, and it is concluded that it is of high importance that homogeneity in type of sampling paper and sampling volume is assured. Piperaquine (PQ) is an antimalarial, increasingly used in artemisinin combination therapy. A method for determination of piperaquine in DBS is presented. By using a monolithic LC column, a very short LC analysis of two minutes per sample is achieved. A method for simultaneous determination of three antiretroviral drugs i.e. lamivudine (3TC), zidovudine (AZT) and nevirapine (NVP), in DBS samples is described. The method is applied to drug determination in two subjects after receiving standard antiretroviral treatment. Conclusion is that the method is suitable for determination of 3TC and NVP, and to some extent for AZT.

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39

Doroudian, Ahmad. "Pharmacokinetics and conjugative metabolism of labetalol stereoisomers in pregnant sheep : a chiral drug case study in pregnancy". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape9/PQDD_0022/NQ38879.pdf.

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40

Carlsson, Björn. "From achiral to chiral analysis of citalopram". Doctoral thesis, Linköpings universitet, Klinisk farmakologi, 2003. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-5217.

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Within the field of depression the “monoamine hypothesis” has been the leading theory to explain the biological basis of depression. This theory proposes that the biological basis of depression is due to a deficiency in one or more of three key neurotransmitter systems, namely noradrenaline, dopamine and serotonin which are thought to mediate the therapeutic actions of virtually every known antidepressant agent. Citalopram is a selective serotonin-reuptake inhibitor (SSRI) used for the treatment of depression and anxiety disorders. Citalopram is a racemic compound, in other words composed of a 50:50 mixture of two enantiomers (S-(+)-citalopram and R-(-)-citalopram) and with one of the enantiomers (S-(+)-citalopram) accounting for the inhibitory effect. At the time of introduction of citalopram the physician needed a therapeutic drug monitoring service to identify patients with interactions, compliance problems and for handling questions concerning polymorphic enzymes and drug metabolism. An achiral analytical separation method based on solid-phase extraction followed by high-performance liquid chromatography (HPLC) was developed for routine therapeutic drug monitoring (TDM) of citalopram and its two main demethylated metabolites. As the data available on citalopram were from achiral concentration determinations and to be able to further investigate citalopram enantiomers effects and distribution, a chiral method for separation of the enantiomers of citalopram and its demethylated metabolites was established. The advances within chiral separation techniques have made measurement of the concentrations of the individual enantiomers in biological fluids possible. The process behind enantioselective separation is however not fully understood and the mechanism behind the separation can be further scrutinized by the use of multivariate methods. A study of the optimization and characterization of the separation of the enantiomers of citalopram, desmethylcitalopram and didesmethylcitalopram on an acetylated ß-cyclodextrin column, by use of two different chemometric programs - response surface modelling and sequential optimization was performed. Sequential optimization can be a quicker mean of optimizing a chromatographic separation; response surface modelling, in addition to enabling optimization of the chromatographic process, also serves as a tool for learning more about the separation mechanism. Studies of the antidepressant effect and pharmacokinetics of citalopram have been performed in adults, but the effects on children and adolescents have only been studied to a minor extent, despite the increasing use of citalopram in these age groups. A study was initiated to investigate adolescents treated for depression, with respect to the steady-state plasma concentrations of the enantiomers of citalopram and its demethylated metabolites. The ratios between the S- and R-enantiomers of citalopram and didesmethylcitalopram were in agreement with studies involving older patients. The concentrations of the S-(+)- and R-(-) enantiomers of citalopram and desmethylcitalopram were also in agreement with values from earlier studies. The results indicate that the use of oral contraceptives may have some influence on the metabolism of citalopram. This might be because of an interaction of the contraceptive hormones with the polymorphic CYP2C19 enzyme. Even though the SSRIs are considered less toxic compared with older monoamine-active drugs like the tricyclic/tetracyclic antidepressants, the risk of developing serious side effects such as ECG abnormalities and convulsions has been seen for citalopram, when larger doses have been ingested. Furthermore, fatal overdoses have been reported where citalopram alone was the cause of death. Data on the toxicity of each of the enantiomers in humans have not been reported and no data on blood levels of the enantiomers in cases of intoxication have been presented. An investigation was initiated on forensic autopsy cases where citalopram had been found at the routine screening and these cases were further analysed with enantioselective analysis to determine the blood concentrations of the enantiomers of citalopram and metabolites. Furthermore the genotyping regarding the polymorphic enzymes CYP2D6 and CYP2C19 were performed. In 53 autopsy cases, we found increasing S/R ratios with increasing concentrations of citalopram. We found also that high citalopram S/R ratio were associated with high parent drug to metabolite ratio and may be an indicator of recent intake. Only 3.8 % were found to be poor metabolizers regarding CYP2D6 and for CYP2C19 no poor metabolizer was found. Enantioselective analysis of citalopram and its metabolites can provide valuable information about the time that has elapsed between intake and death. Genotyping can be of help in specific cases but the possibility of pharmacokinetic interactions is apparently a far greater problem than genetic enzyme deficiency.
On the day of the public defence the status of article IV was: Submitted.

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41

Song, Shin Miin y shinmiin@singnet com sg. "Comprehensive two-dimensional gas chromatography (GCxGC ) for drug analysis". RMIT University. Applied Sciences, 2006. http://adt.lib.rmit.edu.au/adt/public/adt-VIT20080627.114511.

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Separation technologies have occupied a central role in the current practices of analytical methods used for drug analysis today. As the emphasis in contemporary drug analysis shifts towards ultra-trace concentrations, the contribution from unwanted matrix interferences takes on greater significance. In order to single out a trace substance with confidence from a rapidly expanding list of drug compounds (and their metabolites) in real complex specimens, analytical technologies must evolve to keep up with such trends. Today, the task of unambiguous identification in forensic toxicology still relies heavily upon chromatographic methods based on mass spectrometric detection, in particular GC-MS in electron ionisation (EI) mode. Although the combined informing power of (EI) GC-MS has served faithfully in a myriad of drug application studies to date, we may ask if (EI) GC-MS will remain competitive in meeting the impending needs of ultra-trace drug analysis in the fut ure? To what extent of reliability can sample clean-up strategies be used in ultra-trace analysis without risking the loss of important analytes of interest? The increasing use of tandem mass spectrometry with one-dimensional (1D) chromatographic techniques (e.g. GC-MS/MS) at its simplest, considers that single-column chromatographic analysis with mass spectrometry alone is not sufficient in providing unambiguous confirmation of the identity of any given peak, particularly when there are peak-overlap. Where the mass spectra of the individual overlapping peaks are highly similar, confounding interpretation of their identities may arise. By introducing an additional resolution element in the chromatographic domain of a 1D chromatographic system, the informing power of the analytical system can also be effectively raised by the boost in resolving power from two chromatographic elements. Thus this thesis sets out to address the analytical challenges of modern drug analysis through the application of high resolut ion comprehensive two-dimensional gas chromatography (GCeGC) to a series of representative drug studies of relevance to forensic sciences.

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42

Miyake, Yuka. "Synthesis and Functional Evaluation of Novel Chiral Dendrimer-triamine-coordinated Gd-MRI Contrast Agents That Can Act as Molecular Probes". 京都大学 (Kyoto University), 2016. http://hdl.handle.net/2433/215564.

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43

Krait, Sulaiman [Verfasser], Gerhard [Gutachter] Scriba, Oliver [Gutachter] Werz y Schepdael Ann [Gutachter] Van. "Capillary electrophoresis methods for chiral drug analysis and cyclodextrin-guest complexation mechanisms / Sulaiman Krait ; Gutachter: Gerhard Scriba, Oliver Werz, Ann Van Schepdael". Jena : Friedrich-Schiller-Universität Jena, 2021. http://d-nb.info/123135657X/34.

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44

Griffoni, Chiara [Verfasser], Thomas [Gutachter] Dandekar y Katharina [Gutachter] Maniura-Weber. "Towards advanced immunocompetent skin wound models for in vitro drug evaluation / Chiara Griffoni ; Gutachter: Thomas Dandekar, Katharina Maniura-Weber". Würzburg : Universität Würzburg, 2019. http://d-nb.info/1200856333/34.

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45

Tarver, John A. (John Arthur). "Chemical Ionization (CI) GC/MS Analysis of Underivatized Amphetamines Followed by Chiral Derivatization to Identify d and l-Isomers with Ion Trap Mass Spectrometry". Thesis, University of North Texas, 1991. https://digital.library.unt.edu/ark:/67531/metadc504248/.

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An efficient two step procedure has been developed using CI GC/MS for analyzing amphetamines and related compounds. The first step allows the analysis of underivatized amphetamines with the necessary sensitivity and specificity to give spectral identification, including differentiation between methamphetamine and phentermine. The second step involves preparing a chiral derivative of the extract to identify d and 1-isomeric composition.

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46

Arnell, Robert. "Development and Validation of Methods for Characterization of Multi-Component Systems in Preparative LC". Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-7422.

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47

Shamaev, Alexei E. "Synthesis, Photochemical Properties and DNA Binding Studies of DNA Cleaving Agents Based on Chiral Dipyridine Dihydrodioxins Salts". Bowling Green State University / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=bgsu1445859853.

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48

Huang, Shu-hwa y 黃淑華. "Development new chiral derivatizing agent,AFGIT for amine drugs". Thesis, 1997. http://ndltd.ncl.edu.tw/handle/58688638805112283768.

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碩士
台北醫學院
藥學研究所
85
GITC(2,3,4,6-tetra-O-acetyl-b-D-glucopyranosyl isothiocyanate) is one GITCof the most widely applicable chiral derivatizing agent to resolve racemic amines . GITC containing isothiocyanate active moiety can react with those compounds contain amine functional group. Good resolution of the diastereomeric thiourea derivatives is generally achieved by HPLC via UV detection .Due to weak chromophore , GITC is not sensitive enough to be detected in low concentration . In order to improve the detection sensitivity, fluorescent chiral derivatizing agent，CGIT [6-O-(4'- methylcoumarin-7'- methoxycarbonyl)-2,3,4-tri-O- acetyl-a-D-glucopyranosyl isothiocyanate] was developed previously in our laboratory . Now we like to report here the synthesis of another new fluorescent chiral derivatizing agent，AFGIT [6- (9'-aminofluorenyl)-2,3,4-tri-O-acetyl-b-D-glucunopyranosyl isothiocyanate] . Glucuronolactone is served as a starting material for the preparation of AFGIT . Glucuronolactone was reacted with NaOH in 50% CH3OH aqueous to produce sodium glucuronate，and then was acetylated in the presence of p-toluenesulfonic acid . Incoporation of 9-aminofluorene to tetra-O-acetyl glucuronic acid as an amide linkage and following reaction with HBr affored the acetobromoglucuronic acid，subsequent reaction with AgSCN yielded the fluorescent chiral derivatizing agent，AFGIT . Derivatization was performed by reaction of AFGIT with primary or secondary amines in CH3CN for one hour . However amino acids were reacted in 50% aqueous CH3CN catalyzed by triethylamine for one hour . These diastereoisomeric thioureas was separated on a reversed HPLC column (C18) with a fluorescence detector (λex. : 270 nm ,λem. : 310 nm). Mobile phase of 55~70% CH3OH in 0.1% H3PO4 solution for racemic amino acids，60% CH3CN in 0.1% H3PO4 aqueous (v/v) for racemic adrenergic b-blockers，and CH3CN : CH3OH : 0.1% H3PO4 aqueous = 40 : 20 : 40 (v/v/v) for phenethylamines were applied . Twelve racemic amino acids (a =1.04~1.71) , four adrenergic b-blockers (a>1.1)，and four phenethylamines (a=1.05~1.15) were resolved successfully. Comparison of the detection sensitivity of DL-alanine derivatives of AFGIT and GITC, the detection sensitivity of AFGIT derivatives were at least 18 times more stronger then those of GITC derivatives . In conclusion，the new chiral derivatizing agent，AFGIT，is not only useful to resolve the racemic amine drugs or amino acids but also to enhance their detection sensitivity by the developed methods.

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49

Chih-How, Chang y 張志豪. "Chiral separation of imidazole antifungal drugs by capillary electrophoresis: optimization of chiral separation of sulconazole". Thesis, 2000. http://ndltd.ncl.edu.tw/handle/12152470573032593837.

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碩士
國立臺灣大學
藥學研究所
88
Chiral separations of five imidazole antifungal drugs, i.e., econazole, miconazole, isoconazole, sulconazole and sertaconazole, by capillary electrophoresis was developed in this study. Various *-cyclodextrins, including *-cyclodextrin (*-CD), dimethyl-*-cyclodextrin (DM-*-CD), trimethyl-*-cyclodextrin (TM-*-CD), hydroxyethyl-*-cyclodextrin (HE-*-CD), hydroxypropyl-*-cyclodextrin (HP-*-CD) and carboxymethyl-*-cyclodextrin (CM-*-CD) were tested as chiral selectors for the separations of these basic drugs in acidic phosphate buffers. Other parameters relevant to chiral separations such as organic modifiers, organic cations and background electrolyte concentration were also tested to evaluate their effects on separations. Each of the five analytes was found to have its own appropriate cyclodextrin and concentration for chiral separation. Generally speaking, DM-*-CD had the lowest resolving power over the five pairs of enantiomers, while HP-*-CD afforded the best separation except for the sertaconazole enantiomers. The optimum pH was found to be 3.0 for all analytes. The addition of organic modifiers gave no benefit to the separation and mostly worsened the resolution. Change of the buffer cation from sodium to small organic ammonium ions, however, spoiled the resolution and lengthened the migration time. Increasing the sodium ionic strength in buffer solution would improve the enantiomeric separation of isoconazole and sulconazole, with the latter being most benefited because it was the least resolved among the five enantiomeric pairs. To improve the enantiomeric separation of sulconazole, a Plackett-Burman experimental design was used to search for an optimum condition. Experimental results were evaluated with four responses, resolution, migration time, peak efficiency and current. A combined response function, electrophoretic response function (ERF), composed of resolution, migration time and current, was also used to evaluate the overall separation. Following the conditions predicted by the design, the experiment was carried out and the results showed that resolution had little changed but both the migration time and current decreased. Because resolution is of primary importance to enantiomeric separation, the search for a new chiral selector with much better resolution will be continued in our laboratory.

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Lin, Yu-Liang y 林于喨. "Synthesis of the Chiral Polyaniline for Recognition of Non-steroidal Anti-inflammatory Drugs". Thesis, 2007. http://ndltd.ncl.edu.tw/handle/65345477732550976748.

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碩士
國立東華大學
化學系
95
Chiral polyaniline prepared by electrochemical polymerization was studied to explore the addition of N-phenyl–1,4diamine (aniline dimer) on chirality. The polymerization time, ratio of aniline and dopant, pH value, redox states, dopants, and aniline derivatives were studied and optimized for the chirality of polyaniline. The polyaniline film was characterized by cycle voltammetry, UV-Vis, and AFM spectroscopy. Furthermore, the differences of chemical and electrochemical polymerization were compared. The aniline dimer produced the better electroactive and the rate of polymerization was promoted. However, the surface of the polyaniline is rougher than that without aniline dimer addition. Emeraldine salt form were obtained in both methods. The best chirality were achieved as follows : the proportion of aniline and CSA－ is 1 : 1.82, pH 1.80 in no aniline dimer；the proportion of aniline and CSA－ is 1 : 3.64, pH is 1.35 in aniline dimer；0.9V for 100 seconds in electrochemical polymerization；condition at 0.4V. The enantioselectivity of the chiral polyaniline was examed by EQCM and the SPME combined with HPLC was used to analyzed NSAIDs. The (S)-chiral polyaniline showed better binding efficiency for (S)-form NSAIDs than (R)-form, while the inverse was true for the (R)-chiral polyaniline.

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