An Investigation into the Solid State Properties of Olanzapine and Paroxetine HCl and their Solid Dispersion Systems

摘要

Physical characterisation of pharmaceutical solids is an integral aspect of the drug development process and has attracted increased attention over the past decades. Each active pharmaceutical ingredient (API), may exist in different crystalline forms (polymorphs), incorporate water in their structure (pseudopolymorphs) or be converted, intentionally or not, to an amorphous state. As consequence of all this variety of forms, a full toolbox of characterisation techniques is nowadays available, combining high resolution thermoanalytical techniques with highly precise diffraction methods and advanced computational resources.The work presented in this thesis aimed to provide an in-depth understanding of the physicochemical properties of single drug molecules (olanzapine and paroxetine HCl) and final formulated systems in varying physical states including different crystalline entities and amorphous systems. In this work, a combination of thermal (standard differential scanning calorimetry (DSC), modulated temperature DSC (MTDSC), thermogravimetric analysis (TGA) and hot stage microscopy (HSM)), diffraction (X-ray powder diffraction (XRPD) combined, in some studies, with variable humidity (VH) or temperature (VT)) and spectroscopic techniques (attenuated total reflectance–Fourier transform infrared (ATR-FTIR)) were extensively used. Dynamic vapour sorption (DVS), Karl Fischer titration (KFT) and scanning electron microscopy (SEM) were as well of great importance. Dissolution performance and physical stability studies were also evaluated.At first, a thorough investigation into the solid state of paroxetine HCl was performed. Aspects such as the interaction with water and the interconversion between the two crystalline forms, Form I and II, were fully explored. This enabled to successfully clarifying the nature, location and bonding strength of the water molecules in the crystalline structure of paroxetine HCl Form II (Chapter 3). These findings allowed proper recognition of Form II as a non-stoichiometric hydrate with unusual behaviour, and challenges the previous designation as an anhydrous form with a hygroscopic nature. On the other hand, the specific conditions that led to the dehydration of Form I were fully investigated (Chapter 4). The dehydration of Form I was found to require both ultra-dry environment and high temperatures. As a consequence of this process a new anhydrous form of paroxetine HCl has been identified.After this structural characterisation, studies were conducted on the conversion of paroxetine HCl to an amorphous state, either alone (Chapter 5) or molecularly dispersed in polyvinylpyrrolidone vinyl-acetate (PVPVA, Chapter 6). Chapter 5 provided a detailed thermal characterisation using thermodynamic and kinetic parameters of amorphous paroxetine HCl prepared via melt quenching method. The results obtained were then correlated with the stability of this form over storage. In Chapter 6, parameters such as the initial hydration state of the drug (paroxetine Forms I and II) and the methodology used (spray drying (SD) and hot melt extrusion (HME)) were found not only to influence the dissolution rate of the prepared systems but also its physical stability. Finally, the acquired knowledge in the preparation of solid dispersion systems was applied to a Biopharmaceutical Classification System (BCS) Class 2 drug (olanzapine, OLZ) using HME as the selected technology and considering the influence of different polymeric carriers (Chapter 7). This study showed an interesting interplay between the extrusion temperature, drug loading, drug physical state and polymer chemistry that can be further applied to other poorly soluble APIs.To conclude, the research carried out and detailed within this thesis aims to contribute to a better understanding of the complex solid state characterisation of pharmaceutical drugs and formulated systems prepared via solid dispersion methods. To the end, this work has identified several issues and possible areas for future research in the pharmaceutical field.