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- Adolfsson, Åsa
(author)
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Mechanical strength of pharmaceutical compacts : Importance of material characteristics, particle characteristics and compaction pressure on interparticulate bonding structure
- 1998
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Doctoral thesis (other academic/artistic)abstract
- Factors considered important for the interparticulate bonding structure and mechanical strength of pharmaceutical compacts were studied in this thesis.Fractures appear to propagate mainly around rather than through grains during strength testing. Large deviations from theoretical strength values in addition to an effect of particle size were thus obtained when compaction was performed to zero porosity or obtained by extrapolation to zero porosity. When high compaction loads were used, the excess energy was to a large extent used for elastic recovery and/or alteration of the solid-state structure.Filtering out of weak distance forces (intermolecular forces) by compaction in a liquid with a sufficiently high dielectric constant appears to provide reliable information on interparticulate bonding mechanisms. The best correlation between physiochemical properties of the liquids and the gradual decrease in tensile strength of the compacts was achieved using the dielectric constant. The weak distance forces appeared to be screened out when the liquid compaction medium had a dielectric constant of 18. The remaining tensile strength was then believed to be the result of interparticulate bonding by solid bridges for most materials. However, for most pharmaceutical materials, weak distance forces seem to dominate. Of all the materials tested, solid bridges seemed to be the most important bonding mechanism for sodium and potassium chloride. Increasing the particle size and compaction pressure of materials with the capacity to form solid bridges seemed to facilitate the bond formation process. Addition of a dry binder or milling the particles counteracted the formation of solid bridges, probably by reducing the concentration of stress at certain points in the compact, a prerequisite for the establishment of solid bridges.Both the tablet surface area and the interparticulate distance may affect the proportion of external surface area participating in interparticulate bonding. For materials prone to develop solid bridges, the actual surface area involved in bond formation is more important than the space between the particles, i.e. compensation of the tensile strength of a tablet for the surface area and the mean interparticulate distance will probably not reflect the nature of the dominating bond type. However, for the other materials, ranking of the materials according to tensile strength adjusted for surface area and mean interparticulate distance gave a reflection of dominating interparticulate bonding type.
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- Afzelius, Lovisa, 1975-
(author)
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Computational Modelling of Structures and Ligands of CYP2C9
- 2004
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Doctoral thesis (other academic/artistic)abstract
- CYP2C9 is one of our major drug metabolising enzymes and belongs to the cytochrome P450 (CYP) super family. The aim of this thesis was to gain an understanding of the quantitative structure–activity relationships (QSAR) of CYP2C9 substrates and inhibitors. This information will be useful in predicting drug metabolism and the potential for drug–drug interactions. To achieve this, a well characterised data set of structurally diverse, competitive CYP2C9 inhibitors was identified in our laboratory. Several computational methodologies, many based on GRID molecular interaction fields, were applied or developed in order to handle issues such as compound alignment and bioactive conformer selection. First, a traditional 3D QSAR was carried out in GOLPE, generating a predictive model. In this model the selection of a bioactive conformer and alignment was based on docking in a homology model of CYP2C9. Secondly, we introduced the concept of alignment independent descriptors from ALMOND. These descriptors were used to generate quantitatively and qualitatively predictive models. We subsequently derived conformation independent descriptors from molecular interaction fields calculated in FlexGRID. This enabled the derivation of 3D QSAR models without taking into account the selection of an alignment or a bioactive conformer. A subsequent programming effort enabled the conversion of this model back to 3D aligned pharmacophores. Similar alignment independent descriptors were also used in the development of the software MetaSite® that predicts the site of metabolism for CYP2C9 ligands. Finally, as crystal information on this isoform emerged, the performance of molecular dynamics simulations and homology models and the flexibility of the protein were evaluated using statistical analyses.These modelling efforts have resulted in detailed knowledge of the structural characteristics in ligand interactions with the cytochrome P450 2C9 isoform.
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- Alterman, Mathias
(author)
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Design and synthesis of HIV-1 protease inhibitors
- 2001
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Doctoral thesis (other academic/artistic)abstract
- Human Immunodeficiency Virus (HIV) is the causative agent of Acquired Immune Deficiency Syndrome (AIDS). The C2-symmetric HIV-1 protease is one of the prime targets for chemotherapy in the treatment of the HIV infection. Inhibition of HIV-1 protease leads to immature and non-infectious viral particles. Design and synthesis of a number of C2-symmetrical C-terminal duplicated HIV-1 protease inhibitors and subsequent biological evaluation is presented in this thesis.A versatile three step synthetic route has been developed using a carbohydrate as an inexpensive chiral starting material thus allowing inhibitors with the desired stereochemistry to be obtained. By this efficient method a series of tailor-made P2/P2' modified inhibitors were synthesized, and these were evaluated on purified HIV-1 protease and in HIV-1 infected cell assays. Highly active HIV-1 protease inhibitors were identified among the tested compounds. Analyses of the X-ray crystal structures of two of the most active compounds, as complexes with the protease, guided the further design of P1/P1' elongated inhibitors. Substitutions in the para-position of the P1/P1' benzyl groups were promoted efficiently by microwave-irradiated of palladium-catalyzed reactions. Particular modifications in the P1/P1' region of the inhibitors resulted in a 40-fold increase of the anti-viral activity on HIV-1 infected cells. Furthermore, a fast, efficient, and general one-pot microwave enhanced synthesis protocol for transformations of organo-bromides to tetrazoles was developed and applied on the inhibitor scaffold. Attachment of linker molecules to the P1/P1' benzyl groups of one inhibitor was used to develop of sensitivity enhancer tools in surface plasmon resonance biosensor assays. These new assays enable the evaluation of low-molecular weight compounds as HIV-1 protease inhibitors.
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- Amini, Ahmad
(author)
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Enantiomeric separation by capillary electrophoresis : With special emphasis on the partial filling technique
- 1998
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Doctoral thesis (other academic/artistic)abstract
- Capillary electrophoresis as a powerful separation technique was employed for resolution of racemic drugs. Taurodeoxycholate (TDC), different cyclodextrins and α1- acid glycoprotein (AGP) were dissolved in the background electrolyte at low pH (3.0 to 4.0 ) as chiral selectors.Enantioresolutions were based on the principle of micellar electrokinetic chromatography, inclusion complexation and affinity interactions between the enantiomers and TDC, cyclodextrins and AGP, respectively.The influence of chiral selector concentration and type, temperature and addition of organic modifiers on enantioselectivity were studied. The temperature was found to be an important factor for regulation of the enantioresolution.In order to avoid UV-absorbance interferences between AGP as a UV-absorbing chiral selector as well as to reduce consumption of chiral selector solution, the partial filling technique (PFT) was employed. The technique was developed and equations describing the feature of the technique as an efficient separation mode in CE was presented. Parameters such as applied plug length (PLapp) and effective plug length (PLeff) were determined. Equations expressing the relation between the PLeff and selectivity and resolution factors were developed.The PFT was used for determination of association constants between AGP as chiral selector and the enantiomers of disopyramide and remoxipride. The association was strongly temperature dependent, and a maximum in binding was observed at 25°C. The PFT was found to be a very convenient approach for measurement of association constants. To verity the above mentioned technique for evaluation of binding constants, the association constants between methyl-β-cyclodextrin and the enantiomers of orciprenaline at different chiral selector concentrations were measured and compared with the data obtained by the conventional technique. The results illustrate the reliability of the system based on the PFT.
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