Supramolecular derivatisation of new anti-tubercular and antimalarial drug leads

The UCT Drug Discovery and Design Centre, H3D, provided anti-tubercular and antimalarial drug leads that display potent in vitro and in vivo activity, but with unfavourable physicochemical properties. The primary objective of this study was to prepare supramolecular derivatives of the drug leads in an attempt to improve their physicochemical properties. Any new solid forms were to be characterized by a variety of analytical techniques, including X-ray analysis, spectroscopic and thermal techniques. Where possible, such derivatives would be tested for any enhancement in the aqueous solubility or biological activity of the drug lead. The second objective of this study was to employ supramolecular intervention in the early stages of the drug discovery and development process to help streamline the process by distinguishing between compounds that might be amenable to beneficiation via supramolecular modification and those that might not. The crystal structure of a novel anti-tubercular drug lead, DL2, was solved and the compound was fully characterized using thermal and X-ray techniques. This compound displayed very poor solubility in both aqueous and organic media. Phase solubility studies were performed with anti-tubercular drug lead DL3 and selected cyclodextrins (CDs). The apparent solubility of DL3 increased by a factor of more than 300 at the highest concentration of hydroxypropyl-β-CD (HPβCD) and β-CD investigated. Three salts of antimalarial drug lead DL4 and carboxylic acids were prepared. The salts were characterized by X-ray and thermal techniques. A salt of citric acid and DL4 could be prepared by the liquid-assisted grinding method. The equilibrium solubility of this salt was 48 times greater than that of DL4

Relaxation dynamics and crystallization kinetics of glass-forming drugs

Glassy phases play an important role in our daily life and in many industries such as the food, pharmaceutical, and construction and are responsible for certain vital mechanisms in living species. Whereas crystals are solid phases that show periodicity of the constituent atoms or molecules, glasses are disordered solids that lack long-range positional order but behave mechanically like solids. Chapter 1 of the current thesis presents an introduction to the characteristics and dynamics of glassy phases. How they are derived from the liquid phase, and how they transform into the crystalline solid phase, thermodynamically more stable. The temperature at which a liquid transforms to the amorphous (glassy) phase is called the glass transition temperature, Tg. Along this thesis the relaxation dynamics of prilocaine (PLC) and stiripentol (STP), and the isothermal crystallization process of the latter have been experimentally studied. Both PLC and STP are drugs used in medical applications mainly as anesthesia and for the treatment of epilepsy, respectively. The studied materials have been analyzed by Broadband Dielectric Spectroscopy (BDS), Differential Scanning Calorimetry, X-Ray diffraction, Raman and I.R spectroscopy and confocal microscopy. The physical principles of BDS, the main experimental tool employed, are presented in Chapter 2. The details of the experimental set-ups are stated in Chapter 3. In the case of a pharmaceutical product, being able to control and foresee the aggregation phase and dissolution rate of the substance is vital. Many drugs are poorly soluble in water and thus, in biological media. The glass state of a drug is a non-equilibrium state that presents higher free energy than the crystal. This implies, that a glassy drug dissolves more rapidly and can be absorbed in larger amounts. Nevertheless, the higher free energy of glassy phases represents at the same time a major problem for shelf-life, since metastable phases are prone to spontaneously transforming into the stable crystalline state. This is a major problem, since wrong dosage or agglomeration of a drug could render it useless or toxic for the human body. Understanding the glass and crystallization dynamics of drugs, and their interaction with water is key to develop more efficient products. Water is the universal biological solvent. For most materials the addition of water leads to a decrease in viscosity, or equivalently, an increase of molecular mobility, resulting in a lower glass transition temperature Tg (the higher the water content the lower the Tg). This is referred to as the plasticizing effect of water. Chapter 4 presents a detailed analysis of both pure and hydrated prilocaine. Results show that the addition of water to PLC leads to the formation of PLC-water complexes, possibly water-bridged monomers or dimers that increase Tg. This antiplasticizing effect of water on the molecular mobility of a simple glass former represents a significant exception to the alleged universality of water as drug plasticizer. The physico-chemical origins of this behavior have been confirmed by studying the effect of confinement of the pure and hydrated drug in the pores of a nonporous structure (Chapter 5). In the case of STP, not only the glassy dynamics were studied, but also the crystallization process (Chapter 6). A sublinear correlation between the characteristic crystal-growth time and the relaxation time of the cooperative relaxation dynamics of stiripentol was found. This correlation was observed also in other substances, which suggests that it is a general correlation at temperatures above Tg. This may allow predicting a substance's crystallization time as a function of temperature. The results of this thesis provide valuable insight into the kinetics and relaxation dynamics, as well as the phase stability, of both studied drugs that could be general to other amorphous drugs. Global conclusions are outlined in Chapter 7.Las fases vítreas son importantes en la vida diaria, en industrias como la alimentaria, farmacéutica y construcción, y son responsables de mecanismos vitales en organismos vivos. Mientras que los cristales son fases sólidas que muestran periodicidad en sus átomos o moléculas constituyentes, los vidrios son sólidos desordenados que carecen de orden posicional de largo alcance pero que se comportan mecánicamente como sólidos. El cap. 1 introduce las características y dinámica de las fases vítreas. Cómo se derivan de la fase líquida y cómo se transforman en la fase sólida cristalina, termodinámicamente más estable. La temperatura a la que un líquido se transforma en la fase amorfa (vítrea) se denomina temperatura de transición vítrea, Tg. En esta tesis se estudió experimentalmente la dinámica de relajación de prilocaína (PLC) y estiripentol (STP), y el proceso de cristalización isotérmica del último. Ambas sustancias son fármacos utilizados en aplicaciones médicas principalmente como anestesia y para el tratamiento de la epilepsia, respectivamente. Los materiales estudiados han sido analizados por Espectroscopia Dieléctrica de Banda Ancha (BDS), Calorimetría de Barrido Diferencial, Difracción de Rayos X, espectroscopía Raman e I.R y microscopía confocal. Los principios físicos de BDS, la principal herramienta experimental empleada, se presentan en el Cap. 2 y las configuraciones experimentales en el Cap. 3. En productos farmacéuticos es vital controlar y prever la fase de agregación y velocidad de disolución de la sustancia. Muchos medicamentos son poco solubles en agua y, por lo tanto, en medios biológicos. El estado vítreo es un estado de no equilibrio que presenta una mayor energía libre que el cristal. Consecuentemente, un medicamento vítreo se disuelve más rápidamente y puede absorberse mejor. Sin embargo, la mayor energía libre de las fases vítreas representa al mismo tiempo un problema importante para su vida útil, ya que las fases metaestables son propensas a transformarse espontáneamente en el estado cristalino estable. Ésto es un problema importante, ya que la dosificación incorrecta o la aglomeración de un medicamento pueden volverlo inútil o tóxico para el cuerpo humano. Comprender la dinámica vítrea y la cristalización de las drogas, y su interacción con el agua es clave para desarrollar productos más eficientes. El agua es el solvente biológico universal. En la mayoría de los materiales el agregado de agua conduce a una disminución de la viscosidad o a un aumento de la movilidad molecular, dando una Tg más baja (más agua, menos Tg). Esto se conoce como el efecto plastificante del agua. El Cap. 4 presenta un análisis detallado de la PLC pura e hidratada, mostrando que la adición de agua a PLC conduce a la formación de complejos PLC-agua, posiblemente monómeros o dímeros conectados por agua que aumentan la Tg. Este efecto antiplastificante del agua sobre la movilidad molecular de un simple formador de vidrio representa una excepción significativa a la supuesta universalidad del agua como plastificante de fármacos. Los orígenes físico-químicos de este comportamiento se han confirmado al estudiar el efecto del confinamiento del fármaco puro e hidratado en los poros de una estructura no porosa (Cap. 5). En el caso de STP se estudió la dinámica vítrea y el proceso de cristalización (Cap. 6). Se encontró una correlación sublineal entre el tiempo característico de crecimiento del cristal y el tiempo de relajación de la dinámica cooperativa de relajación del STP y en otras sustancias, sugiriendo una correlación general a temperaturas superiores a Tg. Esto podría permitir predecir el tiempo de cristalización de una sustancia en función de la temperatura. Los resultados de esta tesis proporcionan información valiosa sobre la dinámica de relajación y cinética, así como la estabilidad de fase que podrían ser generales para otros fármacosPostprint (published version

Phase equilibria modelling of petroleum reservoir fluids containing water, hydrate inhibitors and electrolyte solutions

Formation of gas hydrates can lead to serious operational, economic and safety problems in the petroleum industry due to potential blockage of oil and gas equipment. Thermodynamic inhibitors are widely used to reduce the risks associated with gas hydrate formation. Thus, accurate knowledge of hydrate phase equilibrium in the presence of inhibitors is crucial to avoid gas hydrate formation problems and to design/optimize production, transportation and processing facilities. The work presented in this thesis is the result of a study on the phase equilibria of petroleum reservoir fluids containing aqueous salt(s) and/or hydrate inhibitor(s) solutions. The incipient equilibrium methane and natural gas hydrate conditions in presence of salt(s) and/or thermodynamic inhibitor(s) have been experimentally obtained, in addition to experimental freezing point depression data for aqueous solution of methanol, ethanol, monoethylene glycol and single or mixed salt(s) aqueous solutions, are conducted. A statistical thermodynamic approach, with the Cubic-Plus-Association equation of state, has been employed to model the phase equilibria. The hydrate-forming conditions are modelled by the solid solution theory of van der Waals and Platteeuw. Predictions of the developed model have been validated against independent experimental data from the open literature and the data generated in this work. The predictions were found to agree well with the experimental data.Joint Industrial Project (JIP) Gran