Crystallization As Studied By Broadband Dielectric Spectroscopy PDF Download

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.