Cocrystallization studies of selected pharmaceutical compounds: Insights into structure, morphology, and intermolecular interactions

Pharmaceutical solids often exhibit complex structural landscapes, where polymorphism and supramolecular interactions play central roles in determining their physical properties and performance. This thesis investigates the design and behavior of cocrystals across three model systems like sulfonamides, indomethacin, and aspartame, using a combination of crystallographic, thermal, and morphological analysis. In sulfonamide–pyridyl systems, the studies reveal a rich diversity of cocrystal structures stabilized by robust hydrogen-bonding synthons, supplemented by chalcogen interactions and π–π stacking. These findings illustrate how subtle variations in coformer geometry and crystallization method can direct supramolecular assembly and, in some cases, lead to polymorphism. In indomethacin, a drug known for its complex polymorphism and needle-like morphology, cocrystallization with structurally related coformers demonstrated that stacking interactions can be modulated to influence crystal growth and recrystallization behavior. This work shows how even minor chemical modifications can redirect crystallization pathways and alter morphology, offering practical strategies for overcoming processing challenges. Aspartame, widely used as an artificial sweetener but hindered by needle-shaped crystals, was shown for the first time to form a structurally characterized cocrystal. The study provides atomic-level insight into how coformers can engage with aspartame’s dominant hydrogen-bonded motifs, pointing to routes for modifying morphology while preserving lattice stability. Finally, ternary crystallization attempts involving sulfonamides, pyridyl derivatives, and carboxylic acids highlighted both the opportunities and limitations of higher-order cocrystaldesign. While ternary solids proved elusive, the screening yielded several new binary cocrystals. Taken together, these findings expand the understanding of how hydrogen bonding, stacking, and chalcogen bonding shape the crystal landscapes of pharmaceutically relevant molecules. The results provide both conceptual insights for crystal engineering and practical guidance for addressing challenges related to polymorphism and morphology in drug development.

Publisher

University of Galway

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CC BY-NC-ND

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University of Galway Theses (PhD Theses)