Contents:

1 Introduction

2 Aims and Objectives

3 Materials and Methods

4 Development and Validation of HighThroughput Crystallisation and Analysis HTCAA Methodology for Physical Form Screening

5 Predicting Crystallisability of Organic Molecules Using Statistical Modelling Techniques

6 Exploring the Crystal Structure Landscape of Olanzapine

7 Exploring the Physical Form Landscape of Clozapine Amoxapine and Loxapine

8 Conclusions and Further Work

Appendix

This thesis investigates a range of experimental and computational approaches for the discovery of solid forms. Furthermore, we gain, as readers, a better understanding of the key factors underpinning solid-structure and diversity. A major part of this thesis highlights experimental work carried out on two structurally very similar compounds. Another important section involves looking at the influence of small changes in structure and substituents on solid-structure and diversity using computational tools including crystal structure prediction, PIXEL calculations, Xpac, Mercury and statistical modeling tools. In addition, the author presents a fast validated method for solid-state form screening using Raman microscopy on multi-well plates to explore the experimental crystallization space. This thesis illustrates an inexpensive, practical and accurate way to predict the crystallizability of organic compounds based on molecular structure alone, and additionally highlights the molecular factors that inhibit or promote crystallization. Common terms and phrases: acetic acid amorphous amoxapine analysis anhydrous approaches arrangement atoms AXPN blue Carbon tetrachloride carried Chem chemical classification clozapine collected colour compounds computational conformation contribution Cryst crystal energy landscape crystal structures crystallisation CZPN descriptors Dihydrate diversity drug effect et al ethanol experimental experiments Figure Florence form II further green Growth H-bonds hydrogen bonding identified interactions intermolecular interactions involving known loxapine LXPN material method mixture molecular molecular pairs molecules monohydrate novel nucleation observed obtained olanzapine organic outcome OZPN packing pharmaceutical phase physical form screening plate plot polymorphs potential prediction present Price properties provides Raman spectra Raman spectroscopy Random range region reported represents respectively salts sample Sect selection showed shown similar solid form solid-state solution Solvate hydrate solvent space space group Stack statistical Table techniques temperature various XRPD