Linking Charge Density Studies with Physicochemical Evaluation for Co-Crystal Pharmaceutical Enhancement

Abstract

This thesis explores how co-crystallisation improves the physicochemical properties of pharmaceutical formulations by linking charge density data from theoretical and experimental studies to physical testing outcomes such as dissolution rates and stability. It addresses the challenge that many marketed drugs still have poor physicochemical profiles. The research aims to refine drug development through understanding co-crystallisation's impact on these properties. Chapter 1 covers the techniques for analyzing co-crystals, such as X-ray diffraction and the role of weak interactions like hydrogen bonds. Chapter 2 discusses physical testing methods, including dissolution rates, solubility, and thermal analysis. Chapter 3 presents a charge density study of a novel co-crystal between salicylic acid and 4,4'-bipyridine, revealing how hydrogen bonding influences lattice energy and stability. Chapter 4 extends this with a theoretical analysis of coformer selection in xanthines, showing how coformer length affects lattice energy and topological properties. Chapter 5 combines theoretical and physical testing of xanthine co-crystals with dicarboxylic acids, demonstrating how charge density data complements physical testing like dissolution rates. Chapter 6 presents a charge density analysis of indomethacin-saccharin co-crystals, showing enhanced stability and solubility compared to indomethacin alone. Finally, Chapter 7 explores the fluconazole-glutaric acid co-crystal, demonstrating improved dissolution rates and stability, supported by molecular dynamic simulations.