Recently, new insights into crystallization prior to actual nucleation have shown interesting results for drugs showing differences in hydrogen bonding or orientation in various polymorphic forms. On the basis of this concept, piroxicam was chosen as a model compound because the two common forms, I and II, show hydrogen bonding between different parts of the molecules and differences in the orientation of molecules in the crystal lattice. The goal of this work is to explore how various methods of controlling polymorphism during production could be employed. The mechanisms behind the nucleation were also explored, and new insights into polymorphic control are documented and discussed. The crystal landscape was mapped for cooling crystallization of piroxicam from acetone/water mixtures (0.5 K/min) and for antisolvent crystallization from acetone with water as the antisolvent. Varying cooling rates and the use of seeding were used to determine if the system was controlled by a single nucleation event or if the initial form was not the determining factor for the produced form. Finally, the use of soluble additives have previously been found to impact the polymorphic form and was thus employed to impact the nucleation rate as well as the formation of the solid forms in batch cooling crystallization.
Bruun Hansen, T., & Qu, H. (2015). Formation of Piroxicam Polymorphism in Solution Crystallization: Effect and Interplay of Operation Parameters. Crystal Growth & Design, 15(9), 4694-4700. https://doi.org/10.1021/acs.cgd.5b01016