Dependence of Heterogeneous Nucleation on Hydrogen Bonding Lifetime and Complementarity

The crystallization of seven active pharmaceutical ingredients (APIs) (acetaminophen (AAP), carbamazepine (CBMZ), caffeine (CAF), phenylbutazone (PBZ), risperidone (RIS), clozapine base (CPB), and fenofibrate (FF)) was studied in the absence and presence of microcrystalline cellulose (MCC) which acted as a heterosurface. Two of the active pharmaceutical ingredients (APIs), namely, AAP and CBMZ, possess hydrogen bond donor (HBD) and hydrogen bond acceptor (HBA) functionalities, whereas the other five possess HBA functionality only. Density functional theory (DFT) and molecular dynamics calculations complemented the experimental study. The smallest nucleation rate enhancement was observed for CBMZ at 1.4 times, and the largest was observed for FF at 16 times. For all the APIs studied, the interfacial energy was similar for crystallizations performed in the presence and absence of the heterosurface. By contrast, the pre-exponential factor was larger by a factor of ca. 2 and more for crystallizations carried ...