POLYMORPH FORMATION OF TOLFENAMIC ACID: AN INVESTIGATION OF PRE-NUCLEATION ASSOCIATION

The majority of pharmaceutical products are formulated as solids in the crystalline state. With the potential to exist in different crystalline modifications or polymorphs, each solid form bears its own physical and chemical properties, influencing directly bioavailability and manufacturability of the final dosage form. In view of the importance of crystalline form selection in the drug development process, it is imperative for pharmaceutical scientists to work arduously on various aspects of polymorphism, ranging from fundamental understanding of the phenomenon at the molecular level to practical utilization of a specific crystalline form. One common feature of organic crystals is the existence of distinct molecular conformations in different polymorphic structures, known as conformational polymorphism. Conformational polymorphs are routinely observed in drug development, produced when crystal growth conditions vary. Crystallization from solution involves nucleation and crystal growth, the mechanisms that influence the polymorphic outcome. The embryonic solute aggregate has been recognized to play a critical role in dictating the final crystal structure, and solution conditions are also known to drastically influence the self-association behavior of solute molecules during crystallization, affecting crystal packing of organic molecules. For the crystal growth of conformational polymorphs, changes in molecular conformation not only determine the growth kinetics, but also influence the nature and strength of interactions present in the crystal structures. How conformation and intermolecular interaction affect each other underlines the intricacy and the wonder of crystal growth of the organic. Thus, the overall goal of this research is to provide the fundamental understanding of the extent to which solution conditions influence the molecular conformation in the solid-state of a model drug, tolfenamic acid. By combining experimental studies with advanced computational tools, this dissertation offers novel insights into solution species during pre-nucleation and molecular packing of conformational polymorphs of tolfenamic acid. In-depth understanding of the underlying connection between molecular conformation and crystal packing will help advance the knowledge required for rational control of crystal growth