| Polymorphism is the ability of a compound to have more than one solid phase. According to McCrone, the number of polymorphs found for a particular compound is directly proportional to the time and money spent looking for them. Polymorphs have different habits, densities, solubilities, dissolution properties, and flow characteristics. For biologically active compounds, polymorphic forms can have unique efficacy and safety profiles. Health regulators, such as the U.S. Food and Drug Administration and the European Medicines Agency, require that prospective license holders characterize and understand the physical and chemical nature of the drug substances they are manufacturing and products they are marketing. This includes understanding the range of polymorphs that are obtainable and their potential safety profiles.; Crystallization is a ubiquitous unit operation in the pharmaceutical industry. The primary operation factors controlling polymorphic crystallization are: supersaturation, temperature, stirring rate, addition rate of anti-solvent, mixing rate in reactive crystallization and the amount of seed crystals. Secondary factors are solvent choice, additives, and pH. The focus of this work is to use seeding (and therefore secondary nucleation) as a tool to obtain polymorph selectivity, particularly investigating the effect of temperature and supersaturation using two different crystallizer schemes.; In our seeded secondary nucleation experiments, we had metastable polymorphs producing stable polymorphs and stable polymorphs producing metastable polymorphs. In order to understand the unexpected results, we applied two secondary nucleation models to the results obtained numerically by the classical nucleation theory: contact secondary nucleation and embryos coagulation secondary nucleation. All previous models developed were for single component systems. We will present an extension of these models to accommodate polymorphic systems. After application of these models, we have gained process knowledge and can make relevant suggestions to improve the outcome of polymorphic crystallization, specifically crystal purity and type of polymorph crystallized. |
