ETD

• amorphous pharmaceuticals
• Broadband Dielectric Spectroscopy
• Elastic Incoherent Neutron Scattering
• glass transition
• Indomethacin
• isothermal crystallization
• mean square dispalcement
• Mitotane
• physical stability
• thermal degradation

Pharmaceutical compounds represent systems of profound scientific interest, not only because of their practical relevance in medicine and human health, but also due to the rich variety of physical phenomena they exhibit. These two dimensions, often considered distinct, are in fact deeply interconnected: the development of safe and effective pharmaceutical products fundamentally depends on a thorough understanding of the physical principles that govern the behavior of their active components.
It is well established that stabilization of a drug in its amorphous state can significantly enhance its bioavailability and dissolution rate. However, the amorphous state is inherently metastable, and over time, the compound tends to revert to its crystalline form. The limited physical stability of amorphous active pharmaceutical ingredients arises from a complex interplay of intrinsic and extrinsic factors, with molecular mobility widely recognized as the most critical determinant. Another issue occurring during the preparation of generic product is thermal degradation. This aspect has been disregarded for many years, since in some cases its occurrence cannot be directly detected, but its effects have a non-negligible impact on the physical and pharmaceutical properties of a generic pharmaceutics.
The central aim of this thesis was to investigate and characterize pharmaceutical compounds, specifically molecules with a molecular mass below 1000 Da, and to assess their dynamical properties using two complementary techniques: Broadband Dielectric Spectroscopy (BDS) and Elastic Incoherent Neutron Scattering (EINS). These methods probe the samples across distinct time- and length- scales, i.e., approximately in the ranges of 1 μs to 1 ks and 0.1 to 100 μm for BDS, and 1 to 100 ps and 0.03 to 0.3 nm for EINS, thus enabling a multiscale perspective on molecular mobility. This combined approach allows for a comprehensive understanding of the relaxation dynamics of the compounds, including their susceptibility to thermal degradation, their crystallization behavior, and the influence of internal dynamics across different timescales on their physical stability. By integrating insights from both techniques, the study aims to elucidate how microscopic motions contribute to macroscopic transformations, with particular relevance to the long-term stability of amorphous pharmaceutical formulations.
This thesis is structured in two main parts. The first part, titled Theoretical Background, introduces the main concepts necessary to understand the physical phenomena under investigation, as well as the experimental techniques employed throughout the study. In particular, Chapter 1 provides a general overview of glass transition and isothermal crystallization, which are central to the physical stability of amorphous pharmaceutical compounds. Chapter 2 offers a description of the two experimental methods used in this work: BDS and EINS, highlighting their respective strengths and the different time- and length- scales they probe.
The second part of the thesis, entitled Experimental Results, presents the findings obtained from the investigation of two pharmaceutical compounds. Chapter 3 focuses on the investigation of a model compound, Indomethacin, which recently has been demonstrated to show thermal degradation upon thermal amorphization procedure. The aim of this chapter is to assess the effect of thermal degradation on the internal dynamics in the timescale from seconds to microseconds, showing the impact that even an apparently small fraction of degraded sample may have. Chapter 4 explores Mitotane physical stability properties by combining BDS and EINS. Both techniques have been used to explore the dynamical properties of this molecule in the supercooled liquid and glassy states, and to have a closer insight into its isothermal crystallization properties. More in details, the effect of the thermal history, i.e. the preparation protocol, has been assessed, showing how a combination of cooling/heating rate and explored temperature interval can impact the physical stability of a generic compound. Based on these evidences, a protocol has been adopted where the influence of the thermal history is minimal, granting the highest reproducibility degree possible, and the emergence of the crystal from the supercooled liquid matrix has been explored with BDS and further investigated with EINS, exploiting the different time and spatial selectivity of the latter, which allowed us to uncover very fine details on the phenomenon of isothermal crystallization. Finally, Chapter 5 provides a synthesis of the results and outlines potential directions for future research, including complementary techniques and further experimental campaigns.