The Role of Cocrystals in Solid-State Synthesis of Imides and the Development of Novel Crystalline Forms of Active Pharmaceutical Ingredients

With a greater understanding of the fundamentals of crystal engineering lays the potential for the development of a vast array of novel materials for a plethora of applications. Addressed herein is the latent potential of the current knowledge base with an emphasis upon cocrystallization and the desire for scientific exploration that will lead to the development of a future generation of novel cocrystals. The focus of this dissertation is to expand the cocrystallization knowledge base in two directions with the utilization of cocrystals in the novel synthetic technique of cocrystal controlled solid-state synthesis and in the development of active pharmaceutical ingredients. Cocrystal controlled solid-state synthesis uses a cocrystal to align the reactive moieties in such a way that the reaction occurs more quickly and in higher yield than the typical solution methodology. The focus herein is upon cocrystal controlled solid-state synthesis of imides where an anhydride and primary amine were the reactive moieties. Forty-nine reactions were attempted and thirty-two resulted in successful imide formation. In addition, the cocrystal was isolated as part of the reaction pathway in three cases and is described in detail. The impact of cocrystals upon active pharmaceutical ingredients is also addressed with a focus upon generating novel crystal forms of lamotrigine and meloxicam. Cocrystallization attempts of lamotrigine resulted in ten novel crystal forms including three cocrystals, one cocrystal solvate, three salts, one solvated salt, a methanol solvate, and an ethanol hydrate. Additionally, cocrystallization attempts of meloxicam afforded seven novel cocrystals. Solubility and pharmacokinetic studies were conducted for a selected set of lamotrigine and meloxicam crystal forms to determine the crystal form with the most desirable properties. Properties between crystal form and cocrystal former were also examined