CONTROLLING IMPURITY INCORPORATION MECHANISMS IN PHARMACEUTICAL CRYSTALLIZATIONS

Crystallization is a commonly used method for separating and purifying the desired active pharmaceutical ingredient (API). The manufacturing of APIs typically involves complex organic syntheses that can result in the generation of byproducts, intermediates, and unreacted reagents. These other substances can act as impurities that have detrimental effects for the API, but most importantly could be hazardous for the patient. Despite the significance of these implications, the mechanisms of impurity incorporation in crystallizations are not well understood. A recent study on 50 pharmaceutical crystallization systems found that the most prevalent mechanisms in which impurities were retained above regulatory thresholds were from either the impurity incorporating into the product lattice and forming a solid solution, or the impurity co-precipitating along with the product as it crystallizes. The research in this dissertation seeks to dive deeper into these mechanisms. It explored the effects of solid solutions on crystal properties such as solubility, morphology, and form stability as well as how process conditions (i.e., mixing and impurity level) affect the selectivity of impurity retention on specific faces of the crystals in a powder. The overall goal of this body of work is to facilitate a more scientific understanding of impurity retention in crystallizations with the aim of developing safer and more robust pharmaceutical medications for human and animal patients.