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 out in the presence of the heterosurface. Arising from this study, a model of heterogeneous crystallization was developed wherein two influencing factors were identified. The first involves the issue of hydrogen bond complementarity between heterosurface and API. Hence, a HBD rich heterosurface will provide a hydrogen-bond mediated option for API cluster formation that would otherwise not be specifically available in solution to APIs possessing HBAs only. The second factor identified is that the lifetime of the hydrogen bond made by an individual API molecule or small API cluster with the heterosurface is up to 1000 times longer than (i) the lifetime of API–API interactions in a solution phase, or (ii) the time required for an API molecule to add to a growing crystal. This lifetime effect arises from the greater stability of an adsorbed species, and this extended lifetime increases the probability that other molecules or small clusters of the API in solution will add to the already adsorbed or attached species, thus encouraging the heterogeneous route to crystallization.