Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2007.

Contents: Chitosan -- Controlled drug delivery -- Indomethacin -- Inotropic gelation -- Tripolyphosphate (TPP) -- Explotab® -- Ac-Di-Sol® -- Vitamin C / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2007.

Improved weight loss interventions are needed to help reduce obesity. One dietary factor that has been effective in increasing weight loss is increased dietary structure. One method for increasing dietary structure is prescribing the frequency in which eating bouts (meals and snacks) occur. Eating frequency (EF) has been inversely related to body mass index (BMI) but the impact of EF on weight loss is unclear. This randomized controlled trial examined the effect of EF on hunger, the relative-reinforcing value of food, energy intake (EI), and weight loss during a 6 month behavioral weight loss intervention. Participants (age: 51.0 ± 9.9 yrs, BMI: 35.5 ± 4.8 kg/m2, 57.8% female, 94.1% white) were randomized to one of two EF prescriptions: 1) Three Meal (n=25): three eating bouts/day; or 2) Grazing (n=26): eat at least 100 kcals every 2-3 hrs. Both groups attended 20 sessions and had identical dietary (1200–1500 kcals/day, < 30% kcals from fat) and physical activity (200 minutes/wk) goals. Hunger, relative-reinforcing value of food, diet, and anthropometric data were collected at 0 and 6 months. Using intent-to-treat analyses, Grazing reported a greater EF (eating bouts in which > 25 kcals were eaten/day) than Three Meal at 6 months (5.8 ± 1.1 eating bouts vs. 3.2 ± 0.6 eating bouts, p<0.001). On a 100-mm visual analogue scale Grazing reported significantly less hunger at 6 months as compared to 0 months (47.9 ± 18.5 mm vs. 56.3 ± 15.7 mm, p<0.05), while Three Meal did not report any changes. There were no significant differences in the relative-reinforcing value of food between groups or over time. EI and BMI were significantly (p<0.001) reduced from 0 to 6 months (EI: 0 months = 2198 ± 692 kcals/day vs. 6 months = 1266 ± 353 kcals/day; BMI: 0 months = 35.5 ± 4.8 kg/m2 vs. 6 months = 30.6 ± 4.9 kg/m2). There were no significant differences in EI or BMI between the groups. An EF of approximately six eating bouts/day may decrease hunger more so than an EF of three meals/day while consuming a low-kcal diet during a behavioral weight loss intervention.

Polymeric excipients are generally the least well-characterized components of pharmaceutical formulations. The aim of this dissertation work is to facilitate the quality-by-design (QbD) approach to pharmaceutical formulation and manufacturing by evaluating the inter-grade and inter-batch variability of pharmaceutical-grade polymeric excipients. Sodium alginate, a widely used polymeric excipient, was selected for evaluation using appropriate analytical methods and test conditions, especially rheological methods. The materials used were six different grades of sodium alginate and an additional ten batches of one of the grades. &lt;br&gt;To compare the six grades, steady shear measurements were conducted on solutions at 1, 2, and 3% w/w, consistent with their use as thickening or binding agents. Small amplitude oscillation (SAO) measurements were conducted on sodium alginate solutions at higher concentrations (4-13% w/w) corresponding to their use in controlled release matrices. In order to compare the ten batches of one grade, steady shear and SAO measurements were performed on their solutions at 2% w/w and 8% w/w, respectively. Results show that rheological properties of sodium alginate solutions are influenced by both molecular weight and chemical composition of sodium alginate. ¡§One-point¡¨ apparent viscosity data obtained at one low concentration and one shear rate is not representative of the complex rheological behavior of various grades of sodium alginate solutions at higher concentrations or other shear rates. The potential interchangeability of these different grades used as thickening or binding agents could be established by comparing the apparent viscosities of their solutions as a function of both alginate concentration and shear conditions. For sodium alginate used in controlled release formulations, both steady shear (at one low concentration, e.g., 2% w/w) and SAO measurements (at one high concentration indicative of polymer gel state, e.g., 8% w/w) are recommended to be performed on sodium alginate solutions to ensure interchangeability. Furthermore, among batches of the same grade, significant differences in rheological properties were observed, especially at the high solution concentration (i.e., 8% w/w). In summary, inter-grade and inter-batch variability of sodium alginate can be determined using steady shear and SAO methods. &lt;br&gt;The influence of inter-grade and inter-batch variability of sodium alginate on the functionality of sodium alginate used in matrix tablets was investigated with a focus on compression properties, swelling, erosion behavior of alginate matrix tablets, and drug release from matrix tablets. The compression behavior of four grades and three batches of sodium alginate were studied by compaction energetics, out-of-die Gurnham, and out-of-die Heckel analysis. It was found that sodium alginates deform less plastically than microcrystalline cellulose (MCC PH102) but similar to lactose anhydrous. Sodium alginates also demonstrate more elastic deformations during compression than both MCC PH102 and lactose anhydrous. Compacts prepared from multiple batches of the same grade varied in porosity. The same tensile strength of compacts can be achieved by compressing the multiple batches to the same porosity. &lt;br&gt;Sodium alginate tablets undergo both swelling and erosion in water. Grades with substantially higher apparent viscosities at low solution concentration exhibit a higher percentage of water uptake and a low percentage of erosion. Those batches not significantly different in their apparent viscosities at low solution concentration but significantly different in viscoelasticity at high solution concentrations do demonstrate significant differences in their swelling and erosion behavior. Acetaminophen release from sodium alginate matrix tablets prepared from the four grades and three batches can be well described by a zero-order equation. Significant differences in release profile were observed among various grades and batches. &lt;br&gt;In conclusion, the inter-grade and inter-batch variability of sodium alginate has a significant influence on the swelling, erosion, and drug release behavior of sodium alginate matrix tablets. Apparent viscosities of sodium alginate solution at low concentration alone are not sufficient to predict the functionality of sodium alginate used in matrix tablets. Viscoelastic properties of sodium alginate solutions at high concentrations indicative of polymer gel state are appropriate to be characterized. &lt;br&gt;Further study was conducted to determine whether sodium alginate solutions¡&brkbar; rheological parameters are relevant to sodium alginate¡&brkbar;s use in the formulation of calcium alginate gels. Among the grades with similar guluronic acid percentage (%G), there is a significant correlation between gel fracture force and apparent viscosity. However, the results for the partial correlation analysis for all six grades of sodium alginate show that gel fracture force is significantly correlated with %G, but not with the rheological properties of the sodium alginate solutions. Studies of the ten batches of one grade of sodium alginate show that apparent viscosities of their solutions do not correlate with gel fracture force while tan &lt;em&gt;f&lt;/em&gt;Ô values are significantly, but minimally, correlated to gel fracture force. Inter-batch differences in the rheological behavior for one specific grade of sodium alginate are insufficient to predict the corresponding calcium alginate gel's mechanical properties. &lt;br&gt;In summary, rheological methods, including steady shear and small amplitude oscillation, are able to identify the inter-grade and inter-batch variability of sodium alginate. Inter-grade and inter-batch variability of sodium alginate could lead to substantial differences in the functionality of sodium alginate in matrix tablets and in calcium alginate gels. Rheological properties of sodium alginate in solution are suggestive of its functionality as thickeners, or as controlled release agent. However, rheological properties of sodium alginate in solution do not seem to be sufficient to predict the mechanical properties of the corresponding calcium alginate gels. / Mylan School of Pharmacy and the Graduate School of Pharmaceutical Sciences / Pharmaceutics / PhD / Dissertation

Nowadays, polymer chemists undertake considerable efforts to achieve the preparation of new macromolecules and a perfect control over the macromolecular engineering, i.e. the mass parameters but also over the chain and end-group compositions, topology, etc… is definitively expected. In addition, more complex architectures, such as brush (co)polymers, jellyfish-like topologies…, are required to improve or drastically modify the physicochemical properties of the materials. As a direct consequence of the development of such complex molecular objects, sophisticated techniques are required for the in-depth characterization of the macromolecules, since the exact compositions and structures should be fully and unambiguously identified. Given the fact that the usual characterization tools such as Nuclear Magnetic Resonance (NMR) and Gel Permeation Chromatography (GPC) are extensively used, their abilities have been intensively developed to account for the increasing complexity and diversity of the targeted molecules. Nevertheless, all the usual techniques are averaging methodologies since they only provide pieces of information about the polymer mixture instead of affording data on the individual macromolecules. Since few decades, mass spectrometry (MS) has become as used as NMR and GPC for polymer characterization. In the context of large molecules analysis, MS undoubtedly underwent an impressive craze with the development of two modern ionization procedures, namely Electrospray Ionization (ESI) and Matrix-assisted Laser Desorption/Ionization (MALDI). Those ionization procedures permit the vaporization of macromolecules allowing the intact polymers to be analyzed without a too extensive level of degradation. ESI and MALDI are often considered as soft ionization methods since they offer the possibility to observe ions corresponding to the intact molecules. After their production in the ion source, ions corresponding to the polymer molecules can be mass analyzed by the mass spectrometer and important parameters such as the molecular weight distribution (Mn and Mw), polydispersity index (PDI), the nature of the monomer units and the end-groups can be derived from the measure of the mass-to-charge ratios of the produced ions. In the first part of the present thesis, we studied the MS behavior of different classes of polymers when submitted to ESI and MALDI ionizations. The investigations were devoted to the validation of MS as a truly reliable methodology for fragile polymers such as aliphatic polyesters for instance. In this context, a preliminary MS investigation on semi-telechelic polyethers revealed the importance of the source parameters for the characterization of polymers presenting fragile moieties. We also demonstrated the huge importance of the matrix molecule selection for the MALDI analyses of polymers. In particular, we introduced a new matrix for the MALDI measurements of electroconjugated polymers such as polythiophenes. After the study of the influence of the source parameters on the MS data, a complete study by single stage MS and double stage MS (MS/MS) on newly synthesized polylactides (PLA) was performed. The PLA samples were prepared following original procedures using carbene as catalyst. Finally, to achieve the MS study of PLA ions, we used ion mobility-mass spectrometry (IM-MS) experiments to obtained information on the tridimensional structure of the gas phase PLA ions. In particular, we put a special emphasis on the influence of the charge and size of the polymer chains on their gas-phase conformations. The conclusions derived from the MS/MS and IM-MS results were fully supported by theoretical calculations. In the second part of the thesis, the acquired MS experience was applied to the fine characterization of macromolecules presenting complex architectures obtained by two different polymerization procedures: (i) cobalt-mediated radical polymerization of inter alia acrylonitrile and vinyl acetate and (ii) ring-opening polymerization (ROP) of lactones using non-organometallic catalysts. In particular, mass spectrometry was used to tune the experimental conditions for the ROP of â-lactones using different phosphazenes as catalysts. As an ultimate conclusion, this work points to the very efficient synergy between polymer synthesis, mass spectrometry and theoretical calculations. We believe that this thesis paves the way for innumerable possibilities in the future.

Reversible addition-fragmentation transfer (RAFT) was used as a controlling technique for studying the aqueous heterophase polymerization. The polymerization rates obtained by calorimetric investigation of ab initio emulsion polymerization of styrene revealed the strong influence of the type and combination of the RAFT agent and initiator on the polymerization rate and its profile. The studies in all-glass reactors on the evolution of the characteristic data such as average molecular weight, molecular weight distribution, and average particle size during the polymerization revealed the importance of the peculiarities of the heterophase system such as compartmentalization, swelling, and phase transfer. These results illustrated the important role of the water solubility of the initiator in determining the main loci of polymerization and the crucial role of the hydrophobicity of the RAFT agent for efficient transportation to the polymer particles. For an optimum control during ab-initio batch heterophase polymerization of styrene with RAFT, the RAFT agent must have certain hydrophilicity and the initiator must be water soluble in order to minimize reactions in the monomer phase. An analytical method was developed for the quantitative measurements of the sorption of the RAFT agents to the polymer particles based on the absorption of the visible light by the RAFT agent. Polymer nanoparticles, temperature, and stirring were employed to simulate the conditions of a typical aqueous heterophase polymerization system. The results confirmed the role of the hydrophilicity of the RAFT agent on the effectiveness of the control due to its fast transportation to the polymer particles during the initial period of polymerization after particle nucleation. As the presence of the polymer particles were essential for the transportation of the RAFT agents into the polymer dispersion, it was concluded that in an ab initio emulsion polymerization the transport of the hydrophobic RAFT agent only takes place after the nucleation and formation of the polymer particles. While the polymerization proceeds and the particles grow the rate of the transportation of the RAFT agent increases with conversion until the free monomer phase disappears.<br><br> The degradation of the RAFT agent by addition of KPS initiator revealed unambigueous evidence on the mechanism of entry in heterophase polymerization. These results showed that even extremely hydrophilic primary radicals, such as sulfate ion radical stemming from the KPS initiator, can enter the polymer particles without necessarily having propagated and reached a certain chain length. Moreover, these results recommend the employment of azo-initiators instead of persulfates for the application in seeded heterophase polymerization with RAFT agents.<br><br> The significant slower rate of transportation of the RAFT agent to the polymer particles when its solvent (styrene) was replaced with a more hydrophilic monomer (methyl methacrylate) lead to the conclusion that a complicated cooperative and competitive interplay of solubility parameters and interaction parameter with the particles exist, determining an effective transportation of the organic molecules to the polymer particles through the aqueous phase. The choice of proper solutions of even the most hydrophobic organic molecules can provide the opportunity of their sorption into the polymer particles. Examples to support this idea were given by loading the extremely stiff fluorescent molecule, pentacene, and very hydrophobic dye, Sudan IV, into the polymer particles.<br><br> Finally, the first application of RAFT at room temperature heterophase polymerization is reported. The results show that the RAFT process is effective at ambient temperature; however, the rate of fragmentation is significantly slower. The elevation of the reaction temperature in the presence of the RAFT agent resulted in faster polymerization and higher molar mass, suggesting that the fragmentation rate coefficient and its dependence on the temperature is responsible for the observed retardation. / Um neue Materialien mit außergewöhnlichen Eigenschaften zu erstellen, muss man in der Lage sein, die Struktur der Moleküle zu kontrollieren, aus denen die Materialien bestehen. Für das Maßschneidern solcher neuer Eigenschaften besitzen Polymere ein großes Potenzial: Dies sind sehr lange Moleküle, die aus einer großen Zahl von kleineren Einheiten aufgebaut sind. Proteine und DNS sind Beispiele für natürliche Polymere; Plastik und Gummi sind Beispiele für künstliche Polymere. Letztere werden üblicherweise durch das Zusammenfügen einer Reihe von kleineren Molekülen, den Monomeren, hergestellt. Schon lange versuchen Wissenschaftler, die Anordnung, Anzahl und Art dieser Monomere zu kontrollieren, die sich in der Struktur der Polymermoleküle widerspiegeln. Die gebräuchlichste Methode zur kommerziellen Produktion von Polymeren ist die so genannte freie radikalische Polymerisation. Die Strukturkontrolle durch diese Methode ist jedoch relativ schwierig und wurde maßgeblich erst im letzten Jahrzehnt entwickelt. Trotz der Existenz einiger effektiver Kontrollmethoden ist ihre industrielle Anwendung bislang sehr beschränkt, weil sie nicht für die Emulsionspolymerisation verwendbar sind. Die Emulsionspolymerisation ist die gängigste Technik in der industriellen Produktion von Polymeren. Es handelt sich dabei um ein vergleichsweise umweltfreundliches Verfahren, denn es werden keine organischen Lösungsmittel verwendet. Stattdessen dient Wasser als Lösungsmittel, in dem die Polymere in Form von kleinen, fein verteilten Partikeln vorliegen. In der Natur kommt dieses Prinzip beispielsweise in Pflanzen bei der Bildung von Kautschuk - allgemein als Latex bezeichnet - vor. Schließlich ist die Emulsionspolymerisation einfach durchzuführen: Das Produkt ist in vielen Fällen gebrauchsfertig, und es gibt viele technische Vorteile im Vergleich zu anderen Herstellungsprozessen.<br><br> Doch bevor die Probleme beim Einsatz von Kontrollmethoden in der Emulsionspolymerisation gelöst werden können, müssen erst ihre Ursachen geklärt werden. Dies ist eine unverzichtbare Vorraussetzung zum Übertragen von Forschungsergebnissen auf das tägliche Leben.<br><br> Ziel dieser Arbeit ist die Untersuchung der Probleme, die für die kontrollierte radikalische Polymerisation in Emulsion von Bedeutung sind. Die wichtigste Fragestellung in der Emulsionspolymerisation zielt auf die Löslichkeit der Reaktionskomponenten in den verschiedenen Phasen, wie z.B. in Wasser oder in den Polymerpartikeln. Die Kontrollmethode der Wahl für diese Arbeit ist "Reversibler Additions-Fragmentierungs Transfer" (RAFT). Die RAFT-Methode ist die modernste Kontrollmethode, und sie ist für viele Reaktionsbedingungen und viele Arten von Monomeren anwendbar.

<p>The focus of this study is to synthesize a novel hinged polymer actuator. The linking molecule (hinge) is phenazine with interconnected dipyrrole units.</p>

The use of catanionic drug-surfactant mixtures was proven to be an efficient novel method of obtaining prolonged drug release from gels. It was shown that various commonly used drug compounds are able to form catanionic mixtures together with oppositely charged surfactants. These mixtures exhibited interesting phase behaviour, where, among other structures, vesicles and large worm-like or branched micelles were found. The size of these aggregates makes them a potential means of prolonging the drug release from gels, as only monomer drugs in equilibrium with larger aggregates were readily able to diffuse through the gel. When the diffusion coefficient for drug release from the formulation based upon a catanionic mixture was compared to that obtained for the drug substance and gel alone, the coefficient was some 10 to 100 times smaller. The effects of changes in the pH and ionic strength on the catanionic aggregates was also investigated, and this method of prolonging the release was found to be quite resilient to variations in both. Although the phase behaviour was somewhat affected, large micelles and vesicles were still readily found. The drug release was significantly prolonged even under physiological conditions, that is, at a pH of 7.4 and an osmolality corresponding to 0.9% NaCl. Surfactants of low irritancy, capric and lauric acid, may successfully be used instead of the more traditional surfactants, such as sodium lauryl sulfate (SDS), and prolonged release can still be obtained with ease. Some attempts to deduce the release mechanism from the proposed systems have also been made using transient current measurements, dielectric spectroscopy, and modelling of the release using the regular solution theory. In these studies, the previous assumptions made concerning the mechanism responsible for the release were confirmed to a large extent. Only small amounts of the drug existed in monomer form, and most seemed to form large catanionic aggregates with the oppositely charged surfactant.

Most states within the EU have some kind of CFC-legislation that allows the state in question to tax its residents for gains accrued within foreign companies that they control. CFC-legislations are usually said to counteract tax avoidance and they generally target only income of companies in low tax regimes. Such tax regimes are however not only found in pure tax havens. Some of the member states of the EU have set up preferential tax regimes, often limited to foreign financial offshore activities. Can it be a restriction of the freedom of establishment in article 43 EC to tax a resident taxpayer on CFC-basis for the income of a company resident in another member state? In the affirmative, can such a restriction be justified and if so, on which ground? Can it perhaps be easier to argue in favour of CFC-rules after the recent judgment of Marks and Spencer where the ECJ seems to have applied a broader ground of justification in respect of the counteraction of tax avoidance? These are some of the main questions dealt with in this thesis.

This thesis presents the CMOS integer-N frequency synthesizer for 5 GHz WCDMA applications with 1.8V power supply. The frequency synthesizer is fabricated in a TSMC 0.18£gm CMOS 1P6M technology process. The frequency synthesizer consists of a phase-frequency detector, a charge pump, a low-pass loop filter, a voltage control oscillator, an auto-band selection, and a pulse-swallow divider. In pulse-swallow divider, this thesis use true single phase clock DFF proposed by Yuan and Svensson to work on high frequency region and to save the circuit area and power. This thesis also proposes an auto-band selection circuit to control the output frequency more precise and easier, and it can also reduce the frequency drift effect caused by technology process or temperature variation.