The nucleation of a crystalline phase is the first step in solution crystallization. From a mechanistic point of view, nucleation has been, and still is, a highly debated area. Classical and nonclassical theories have been presented that describe the arrangement of the first molecules towards a stable crystalline nucleus. The nucleation is known to be stochastic and unpredictable and has been responsible for numerous surprises in pharmaceutical development. One of the most notable and impactful examples is of course the sudden emergence of Form II of Ritonavir in the 1990s. Although known to impact nucleation, the presence of soluble components, e.g. impurities, have been comparably less studied. Existing literature largely suggests that impurities/additives adsorb on the emerging interfaces of the clusters and prevent further growth into stable nuclei. However, their role in nucleation is far from understood.
Provided in this presentation is an alternate approach to study nucleation, which is based on compositional analyses of the solid phase during crystallization. The common organic compound salicylic acid has been crystallized in the presence of five structurally similar compounds that mimic structurally similar impurities in a pharmaceutical crystallization. Through controlled experiments varying both the seed load and supersaturation ratio, it is demonstrated that enhancing the nucleation rate leads to larger extent of incorporation of impurities in the solid phase. These observations are used in concert with metastable zone width data to show that nucleation of salicylic acid is fundamentally a multicomponent phenomenon. Furthermore, the simulated impurities are known to form crystalline solid solutions (CSS) with salicylic acid and thus impact the thermodynamic properties of the formed solid phase. This results in quantifiable solubility increases in the solvent system used for crystallization. The solubility-enhancing effect from the CSS is used to determine the de facto supersaturation in crystallization, which leads to surprising conclusions.
