This thesis aimed to investigate the features and properties of the ground states, transient species and photoproducts involved in the photophysical and photochemical processes for four kinds of drug compounds: lomefloxacin (LF), norfloxacin (NF), tiaprofenic acid (TPA), and flurbiprofen (Fp). The investigation used femtosecond transient absorption (fs-TA), nanosecond transient absorption (ns-TA), UV/Vis absorption spectra (UV/Vis), nanosecond transient resonance Raman (ns-TR2) and nanosecond time-resolved resonance Raman spectroscopy (ns-TR3), as well as density functional theory (DFT) calculations. Although many previous investigations have indicated that photo-defluorination or photo-decarboxylation reactions may account for the phototoxicity for these compounds, detailed information on the mechanisms remains unclear. In this thesis, the photo-defluorination reaction of LF was explored in neutral water at pH 7.2. The fs-TA results revealed that the lowest lying excited singlet state species (S1) partially decayed into the ground state through fluorescence emission and partially underwent cleavage of the carbon-fluorine bond at position 8 to generate into a singlet aryl cation. Subsequently, intersystem crossing (ISC) allowing the transformation from singlet cation to triplet carbene was observed. Finally, a cyclization reaction with the N-ethyl chain took place for the triplet carbene to generate the final product. The mechanism underlying NF phototoxicity involves a photo-defluorination reaction in neutral water (pH=7.2). The fs-TA spectra indicated that the S1 underwent efficient ISC to swiftly transform into lowest excited triplet (T1) The ns-TA gained under nitrogen-saturated condition observed a new transient species produced from T1 that was proposed to be a transient species derived from the photo-defluorination reaction involving a SN2Ar* mechanism. The photo-defluorinated product ultimately experienced an ISC process to produce the final product. The photo-decarboxylation mechanism of TPA was studied in a neutral phosphate buffered solution (PBS). The fs-TA data revealed that S1 went through an efficient ISC to rapidly transform into T1 that then undergoes a photo-decarboxylation reaction to produce a triplet biradical species (denoted as TB3). The ns-TA and ns-TR3 results supplied evidence of the protonation process of TB3 that produces the neutral species (denoted as TBP3) that then decayed through ISC to give rise to the singlet TBP species, which underwent further reaction to make the final product (DTPA). The photo-decarboxylation reaction of Fp was explored in pure acetonitrile (MeCN). The second excited singlet (S2) went through internal conversion (IC) to decay to S1. Intriguingly, three different pathways for S1 decay co-exist. One pathway is fluorescence emission and the second is an ISC process. The third pathway is the homolysis of the carbon α bond reaction that proceeds to generate two radical species, one being a carboxyl species and the other being the residual, denoted as FpR that was liable to be oxidized under an oxygen-saturated condition to yield a new radical species with the addition of one oxygen molecule which is denoted as FOR that then experienced intramolecular hydrogen transfer (IHT) and dehydroxylation (DHO) to produce the final product. / published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

The aim of this study was to investigate the effect of different penetration enhancers containing essential fatty acids (EFAs) on the transdermal delivery of flurbiprofen. Flurbiprofen was used as a marker / model compound. Fatty acids were chosen as penetration enhancers for their ability to reversibly increase skin permeability through entering the lipid bilayers and disrupting their ordered domains. Fatty acids are natural, non-toxic compounds (Karande & Mitragotri, 2009:2364). Evening primrose oil, vitamin F and Pheroid™ technology all contain fatty acids and were compared using a cream based-formulation. This selection was to ascertain whether EFAs exclusively, or EFAs in a delivery system, would have a significant increase in the transdermal delivery of a compound. For an active pharmaceutical ingredient (API) to be effectively delivered transdermally, it has to be soluble in lipophilic, as well as hydrophilic mediums (Naik et al., 2000:319; Swart et al., 2005:72). This is due to the intricate structure of the skin, where the stratum corneum (outermost layer) is the primary barrier, which regulates skin transport (Barry, 2001:102; Moser et al., 2001:103; Venus et al., 2010:469). Flurbiprofen is highly lipophilic (log P = 4.24) with poor aqueous solubility. It has a molecular weight lower than 500 g/mol indicating that skin permeation may be possible, though the high log P indicates that some difficulty is to be expected (Dollery, 1999:F126; Hadgraft, 2004:292; Swart et al., 2005:72; Karande & Mitragotri, 2009:2363; Drugbank, 2012). In vitro transdermal diffusion studies (utilising vertical Franz diffusion cells) were conducted, using donated abdominal skin from Caucasian females. The studies were conducted over 12 h with extractions of the receptor phase every 2 h to ensure sink conditions. Prior to skin diffusion studies, membrane release studies were performed to determine whether the API was released from the formulation. Membrane release studies were conducted over 6 h and extractions done hourly. Tape stripping experiments were performed on the skin circles after 12 h diffusion studies to determine the concentration flurbiprofen present in the stratum corneum and dermisepidermis. The flurbiprofen concentrations present in the samples were determined using high performance chromatography and a validated method. Membrane release results indicated the following rank order for flurbiprofen from the different formulations: vitamin F > control > evening primrose oil (EPO) >> Pheroid™. The control formulation contained only flurbiprofen and no penetration enhancers. Skin diffusion results on the other hand, indicated that flurbiprofen was present in the stratum corneum and the dermisepidermis. The concentration flurbiprofen present in the receptor phase of the Franz cells (representing human blood) followed the subsequent rank order: EPO > control > vitamin F >> Pheroid™. All the formulations stipulated a lag time shorter than that of the control formulation (1.74 h), with the EPO formulation depicting the shortest (1.36 h). The control formulation presented the highest flux (8.41 μg/cm2.h), with the EPO formulation following the closest (8.12 μg/cm2.h). It could thus be concluded that fatty acids exclusively, rather than in a delivery system, had a significant increase in the transdermal delivery of flurbiprofen. / Thesis (MSc (Pharmaceutics))--North-West University, Potchefstroom Campus, 2013.

The aim of this study was to investigate the effect of different penetration enhancers containing essential fatty acids (EFAs) on the transdermal delivery of flurbiprofen. Flurbiprofen was used as a marker / model compound. Fatty acids were chosen as penetration enhancers for their ability to reversibly increase skin permeability through entering the lipid bilayers and disrupting their ordered domains. Fatty acids are natural, non-toxic compounds (Karande & Mitragotri, 2009:2364). Evening primrose oil, vitamin F and Pheroid™ technology all contain fatty acids and were compared using a cream based-formulation. This selection was to ascertain whether EFAs exclusively, or EFAs in a delivery system, would have a significant increase in the transdermal delivery of a compound. For an active pharmaceutical ingredient (API) to be effectively delivered transdermally, it has to be soluble in lipophilic, as well as hydrophilic mediums (Naik et al., 2000:319; Swart et al., 2005:72). This is due to the intricate structure of the skin, where the stratum corneum (outermost layer) is the primary barrier, which regulates skin transport (Barry, 2001:102; Moser et al., 2001:103; Venus et al., 2010:469). Flurbiprofen is highly lipophilic (log P = 4.24) with poor aqueous solubility. It has a molecular weight lower than 500 g/mol indicating that skin permeation may be possible, though the high log P indicates that some difficulty is to be expected (Dollery, 1999:F126; Hadgraft, 2004:292; Swart et al., 2005:72; Karande & Mitragotri, 2009:2363; Drugbank, 2012). In vitro transdermal diffusion studies (utilising vertical Franz diffusion cells) were conducted, using donated abdominal skin from Caucasian females. The studies were conducted over 12 h with extractions of the receptor phase every 2 h to ensure sink conditions. Prior to skin diffusion studies, membrane release studies were performed to determine whether the API was released from the formulation. Membrane release studies were conducted over 6 h and extractions done hourly. Tape stripping experiments were performed on the skin circles after 12 h diffusion studies to determine the concentration flurbiprofen present in the stratum corneum and dermisepidermis. The flurbiprofen concentrations present in the samples were determined using high performance chromatography and a validated method. Membrane release results indicated the following rank order for flurbiprofen from the different formulations: vitamin F > control > evening primrose oil (EPO) >> Pheroid™. The control formulation contained only flurbiprofen and no penetration enhancers. Skin diffusion results on the other hand, indicated that flurbiprofen was present in the stratum corneum and the dermisepidermis. The concentration flurbiprofen present in the receptor phase of the Franz cells (representing human blood) followed the subsequent rank order: EPO > control > vitamin F >> Pheroid™. All the formulations stipulated a lag time shorter than that of the control formulation (1.74 h), with the EPO formulation depicting the shortest (1.36 h). The control formulation presented the highest flux (8.41 μg/cm2.h), with the EPO formulation following the closest (8.12 μg/cm2.h). It could thus be concluded that fatty acids exclusively, rather than in a delivery system, had a significant increase in the transdermal delivery of flurbiprofen. / Thesis (MSc (Pharmaceutics))--North-West University, Potchefstroom Campus, 2013.

This thesis is centred around sequential C-C bond forming processes using oxygenated electrophiles. A major part of this research focuses on the constructive deoxygenation of 2-methoxyphenol (guaiacol), a major breakdown product of the renewable feedstock, lignin. 1,2-dielectrophiles are known to be challenging substrates for catalysis if both leaving groups are of similar reactivity, however high selectivity was observed in the palladium- catalysed Grignard cross-coupling of 2-methoxyphenyl-1H-imidazole-1-sulfonate. The previously untested Grignard cross-coupling catalyst, [PdCl₂(Xylyl-Phanephos)], was found to be highly active. A 2-benzoxazolyl functionality was shown to be an excellent directing group for the chelation-controlled nucleophilic aromatic substitution of aryl methyl ethers. However, this modified Meyers reaction is limited to aryl ethers containing an ortho-chelating group. To expand the ether scope, nickel-catalysed Grignard cross-coupling was studied. [NiCl₂(PⁿBu₃)2] showed increased activity in the Grignard cross-coupling of challenging ortho-substituted anisoles compared to the well-renowned [NiCl₂(PCy₃)2] and several Ni0 -NHC systems, with a ligand steric effect demonstrated. The success of [NiCl₂(PⁿBu₃)2] was extended to more activated methoxynaphthalene substrates, in which the lowest reported catalyst loadings (0.1-0.25 mol%) were reported. Induction periods at 0.1 mol% suggested the requirement of inorganic Lewis-acidic magnesium salts to be formed in situ before any considerable activity was observed. Further work is required to increase reaction and ether scope, but this work provides a basis for exploiting lignin- derived phenols as a framework in the synthesis of functionalised chemicals of higher value. The final results chapter concerns an alternative sequential C-C bond forming process using another oxygenated electrophile. [PdCl₂((S)-Xylyl-Phanephos)] was used to accomplish a Grignard cross-coupling of vinyl tosylate, with the product then subjected to a highly enantioselective methoxycarbonylation using the same catalyst. This lead to a concise synthesis of (S)-Flurbiprofen.

The design of the proposed study was to administer R-FB to 72-day old Min/+ mice for up to 42 days. In order to capture the process of tumor reduction, animals were necropsied at various time points. At each time point animals were evaluated for tumor loads and presence of apoptotic cells along the small intestine. Studies have shown that when R-flurbiprofen (R-FB) is administered in the Min/+ mouse model it can cause the prevention and regression on intestinal tumors.

No / The kinetics of the dissociation is fundamental to the formation and the in vivo performance of cyclodextrin supramolecules. The individual determination of the apparent dissociation rate constant (kd,app) using high performance affinity chromatography (HPAC) is a tedious process requiring numerous separate studies and massive data fitting. In this study, the multianalyte approach was employed to simultaneously measure the kd,app values of three drugs through one injection based on the investigation of the dependence of drug-cyclodextrin interaction kinetics on the mobile phase composition. As a result, the kd,app values increased when decreasing the ion strength, increasing the ionization of drugs and adding extra organic solvents. The values of kd,app for acetaminophen, phenacetin and S-flurbiprofen estimated by the multianalyte approach were 8.54+/-1.81, 5.36+/-0.94 and 0.17+/-0.02s(-1), respectively, which were in good agreement with those determined separately (8.31+/-0.58, 5.01+/-0.42 and 0.15+/-0.01s(-1)). For both of the single and multiple flow rate peak profiling methods, the results of the multianalyte approach were statistically equivalent with that of the single compound analysis for all of the three drugs (p>0.05). The multianalyte approach can be employed for the efficient evaluation of the drug-cyclodextrin kinetics with less variance caused by cyclodextrin column bleeding.

All over the world, societies are facing rapidly aging populations combined with a growing number of patients suffering from Alzheimer’s disease (AD). One focus in pharmaceutical research to address this issue is on the reduction of the longer amyloid-β (Aβ) fragments in the brain by modulation of γ-secretase, a membrane-bound protease. R-Flurbiprofen (tarenflurbil) was studied in this regard but failed to show significant improvement in AD patients in a phase 3 clinical trial. This was mainly attributed to its low ability to cross the blood–brain barrier (BBB). Here, we present the synthesis and in vitro evaluation of a racemic meta-carborane analogue of flurbiprofen. By introducing the carborane moiety, the hydrophobicity could be shifted into a more favourable range for the penetration of the blood–brain barrier, evident by a logD7.4 value of 2.0. Furthermore, our analogue retained γ-secretase modulator activity in comparison to racemic flurbiprofen in a cell-based assay. These findings demonstrate the potential of carboranes as phenyl mimetics also in AD research.

No / PURPOSE: Self-emulsifying systems (SES) emulsify spontaneously to produce fine oil-in-water emulsion when introduced into aqueous phase. The self-emulsification process plays an important role during formation of emulsion. The objective of current work was to understand and explore the inner structuration of SES through controlled hydration and further to study the influence of additive on the same which ultimately governs performance of final formulation in terms of droplet size. METHODS: Droplet size of final formulations containing structural analogues of ibuprofen was determined. Microstructural properties of intermediate hydrated regimes of SES were investigated using techniques such as small angle X-ray scattering, differential scanning calorimetry and rheology. RESULTS: The current work established inverse relationship between droplet size of the formulations containing structural analogues of ibuprofen and their Log P values. Microstructural analysis of intermediate hydrated regimes of the prepared samples showed formation of local lamellar structure. Structural analogues of ibuprofen significantly altered microstructure of lamellae which was well correlated with the droplet size of final formulations. In vitro drug release study showed increase in dissolution rate of lipophillic drugs when formulated as SES. CONCLUSION: The current work emphasizes the fact that tailor-made formulations can be prepared by controlling the properties of intermediate regimes.