Rationalizing the Influence of Solvent on the Nucleation of Griseofulvin through Classical and Nonclassical Pathways

The effect of solvent on active pharmaceutical ingredient (API) nucleation behavior is system-dependent. A better understanding of the role of the solvent in nucleation could help predict and control crystallization. In this work, induction time experiments, spectroscopic analysis, and dynamic light scattering were used to explore the influence of solvent on the polymorphic landscape and the nucleation behavior of griseofulvin (GSF), a medium-sized, flexible, model API. Based on a total of 2960 induction time experiments, the relative ease of nucleation was characterized in three solvents commonly used in the pharmaceutical industry: methanol (MeOH), acetonitrile (ACN), and n-butyl acetate (nBuAc). GSF crystallized as stable Form I in MeOH and as solvated forms in both ACN and nBuAc. GSF nucleated most easily in ACN, followed by nBuAc, while nucleation was most difficult in MeOH. This order was found to correlate with increasing interfacial energy, which was found to be lower in ACN, intermediate in nBuAc, and higher in MeOH, based on a classical evaluation. However, in contrast to classical nucleation theory, which suggests that higher nucleation rates are associated with larger pre-exponential factors, the pre-exponential factor was found to be highest in MeOH, while it remained comparable in ACN and nBuAc. An analysis of the GSF solutions used in the nucleation studies confirmed the presence of mesoscale clusters in ACN and in nBuAc, but not in MeOH. The size and concentration of mesoscale clusters in ACN solution were higher than those in nBuAc, which could explain the higher nucleation rate observed in ACN if the nonclassical nucleation pathway is considered for these solvents.