Templated nucleation of acetaminophen on spherical excipient agglomerates.

We investigated the effect of spherical agglomeration of heterogeneous crystalline substrates on the nucleation of acetaminophen (AAP). Optical and electron microscopy showed that the surface morphologies of single crystal triclinic lactose and D-mannitol differed significantly from their counterparts formed via spherical agglomeration. Spherical agglomerates of lactose were shown to enhance the nucleation rate of acetaminophen (AAP) by a factor of 11 compared to single crystal lactose; however, no such enhancement was observed for D-mannitol. X-ray powder diffraction identified the presence of new crystal faces of lactose present only in the spherical agglomerates However, D-mannitol did not show any significant change in crystal morphology. The new crystal faces of triclinic lactose were analyzed using geometric lattice matching software and molecular dynamics simulations to establish any new and significant epitaxial matches between lactose and AAP. A coincident lattice match and a large favorable energy interaction from hydrogen bonding were observed between the (141¯) and (001) crystal faces of lactose and AAP, respectively. The enhanced nucleation kinetics, X-ray data, and computational studies indicated that the spherical crystallization of lactose exposed the (141¯) face on the surface of the agglomerates, which subsequently enhanced the nucleation rate of AAP through geometric lattice matching and molecular functionality. This study highlights the importance of exploring different heterogeneous substrate morphologies for enhancing nucleation kinetics.