Extended Lifetime of Molecules Adsorbed onto Excipients Drives Nucleation in Heterogeneous Crystallization

[Image: see text] Monte Carlo (MC) and molecular dynamics (MD) computer simulations were used to investigate the role of adsorption during seeded and heterogeneous crystallization. The simulations characterized the range of adsorption energies and configurations encountered during adsorption of individual molecules of active pharmaceutical ingredients (APIs), with varying hydrogen-bonding tendencies, onto seed and heterosurfaces. Specifically, the adsorption of acetaminophen (AAP), carbamazepine (CBMZ), fenofibrate (FF), phenylbutazone (PBZ), clozapine (CPB), and risperidone (RIS) was simulated on selected crystallographic facets of their own crystals as examples of seeded crystallizations and on lactose or microcrystalline cellulose (MCC) substrates as heterosurfaces. The MC screening provided adsorption enthalpies in the range of −59 to −155 kJ mol(–1) for these APIs on lactose, generally increasing as the molar mass of the API increased. The corresponding values predicted for adsorption of each API onto its own crystal were in the range of −92 to −201 kJ mol(–1). More detailed MD simulations performed in methanol showed adsorption free energies for RIS on MCC in the range of −37 to −50 kJ mol(–1) with strong molecule–surface complexation lifetime of tens of nanoseconds on the (010) face of MCC. This extended lifetime is a key feature in understanding the mechanism of heterogeneous crystallization. A well-formed nucleus is generated on the surface starting with a single adsorbed molecule. Individual or small clusters add to the adsorbed species. This addition is facilitated by the extended lifetime of the adsorbed molecule, which is several orders of magnitude greater than the time required for additional molecules to assemble and grow into a stable nucleus attached to the heterosurface.