Calorimetry and electron diffraction of molecular compounds of pharmaceutical interest

Pharmacology, as a discipline, has existed since ancient times and has as primary purpose the treatment of human diseases: at the beginning, herbs were at the basis of this discipline, but, with the evolution of chemistry, it was possible to isolate the active principle, namely a molecule, useful for treating illnesses. Nowadays, scientists have developed several ways to treat diseases: depending on the specific application, it is possible to use as active principle molecules, proteins, nanoparticles and so on. This thesis poses its focus on molecular compounds of pharmaceutical interest, namely molecules with molecular mass of less than 1000 Da. Traditionally, pharmaceuticals have been prepared in their crystalline state due to their physical stability upon long term storage. Later on, it has been discovered that the amorphous state grants a higher water solubility to the active principle, increasing its bioavailability and speeding up its intake by the body. However, the use of glassy pharmaceuticals in practical applications is hampered by the reverse of the material to the crystalline state: since the glassy state is metastable, reverse to the crystalline state can take from a couple of hours to months, even if the sample is stored at temperature far below the glass transition temperature. On top of that, most of the recently discovered active principles have a poor water solubility, making the amorphous state desirable for their formulation. These issues have involved significant efforts in the pharmaceutical sector. However, they have been addressed on a time-consuming, case-by-case basis, using different methods and formulation strategies, with an overall slowdown in the production process. On the other hand, there is lack of a general understanding of the basic principles ruling the phenomena involving pharmaceutical materials, making the case-by-case approach the only possible route. In fact, despite the knowledge of the behaviour of the specific active ingredient is of utmost importance for the successful development of the final product, a more general approach is desirable to speed up formulation and development and formulation of new pharmaceuticals. Indeed, a thorough understanding of these phenomena would make the development of new drugs faster and less diffcult, thanks to an approach based on the use of generalised rules. This thesis is an experimental study of some of the phenomena associated with pharmaceutical compounds, with the aim of shedding new light on them from a basic science point of view and opening new perspectives on old questions. The experimental studies have been carried out mainly with two techniques, differential scanning calorimetry (conventional and fast) and electron diffraction. The first gives information about the thermodynamics of the sample under exam, enabling the study of crystallization kinetics, amorphization, physical ageing and polymorphism, whereas the latter is about the crystalline structure of the compound, i.e. the three-dimensional arrangement of the molecules in space. Even though these information can appear very different in nature, they are closely linked because the crystalline structure influences the thermodynamic properties of the specimen and vice versa. Additionally, broadband dielectric spectroscopy and neutron spectroscopy have been employed to gather information on the dynamics of the samples under investigation. Indeed, regardless of the phenomenon being considered, the combination of dynamic (spectroscopic techniques), thermodynamic (DSC/FDSC) and structural (electron diffraction) information provides a unified view of the phenomenon, whose interpretation would be biased or incomplete without at least one of the three perspectives. This thesis is divided in four chapters, each section discussing a specific topic. The first chapter gives to the reader the theoretical background of the physical phenomena investigated. Details about the experimental techniques and data analysis are provided in the second chapter. The third chapter exposes and critically discusses the results obtained during my PhD period, highlighting the future perspectives of the specific study when needed. The last chapter is devoted to make a summary of the work done, the main achievements and future perspectives.