Welcoming Remarks

The primary purpose of crystallization in the pharmaceutical industry is purification. Crystallization is relied on across the entire synthetic scheme from regulatory starting materials (RSMs) to active pharmaceutical ingredients (APIs) to remove undesired impurities and isolate the desired product with the right quality at scale. Impurities are present at all stages of development and exist in different forms, e.g., inorganic and organic impurities, reaction side-products, unreacted starting materials, chiral impurities, dimers and polymers, degradation products and residual solvents. The perhaps most detrimental class of impurities are the so-called genotoxic impurities (GTIs), which typically need to be controlled at ppm levels. Historically, the rejection of impurities by crystallization has been carried out more or less empirically, where spike and purge studies are carried out as part of the control strategy. The solvent and procedure for the crystallization were selected based on the purity profiles of the product before and after isolation, with little insights of the underlying mechanisms. As a result, surprises are not uncommon leading to unexpected deviations and purity issues throughout the different development phases.

This presentation aims to provide an in-depth analysis of the recent advances that has been made in understanding the role of impurities in crystallization. The predominant modes of impurity retention are discussed together with effective strategies that can be implemented in pharmaceutical development. Particular focus is given to crystalline solid solutions (CSSs) where the guest molecules (impurity) are incorporated into the crystal lattice of the host (product). Examples are provided of their structural properties and how the molecular substitution translates into tangible thermodynamic changes, such as solubility and melting properties, which are critical to solid form understanding and process development. Through visualization of binary phase diagrams, it is shown how polymorphic structures can coexist or shift in thermodynamic stability across larger temperatures and compositions, leading to the appearance or disappearance of new polymorphs. Finally, crystallization of an established CSS-forming system is presented that evaluates the kinetics of nucleation and crystal growth in the presence of impurities.