Experimental and Mechanistic Study of the Heterogeneous Nucleation and Epitaxy of Acetaminophen with Biocompatible Crystalline Substrates

The presence of different heterogeneous surfaces can directly influence the nucleation kinetics, crystal growth, and morphology of active pharmaceutical ingredients (APIs). However, a mechanistic understanding of heterogeneous nucleation remains lacking. Herein, we report the use of biocompatible crystalline heterogeneous surfaces to enhance the nucleation rates of the model API compound acetaminophen (APAP). We also report experimental and computational studies of the epitaxial growth mechanism of APAP on different substrates. Five crystalline substrates, namely, d-galactose (DGAL), the α and β forms of d-mannitol (DMAN), α-lactose monohydrate (LMH), and xylitol (XYL) were selected because they contain a similar functionality: a high density of hydroxyl groups per molecule. We measured the induction times in the presence of the substrates and used the results to rank the substrates based on their ability to enhance the nucleation of APAP. While all selected substrates enhanced the nucleation rates, XYL was particularly effective and enhanced the nucleation rate by a factor of 10 (average induction time: 85 min) relative to bulk nucleation (average induction time: 885 min). To determine the mechanism underlying the enhanced heterogeneous nucleation, we analyzed grown crystals using single crystal X-ray diffraction (SCXRD) and developed computational models of APAP–substrate interactions. Previously developed computational techniques, which are based solely on the level of lattice matching (geometric term) and ignore the importance of chemical interactions (energy term) between the crystallizing API and the substrate, were not effective in predicting and explaining our experimental results. Herein, we present a novel computational method that contains both energy and geometry terms to describe the nucleation of APAP on different crystalline substrates. First, we studied the energetics of the association of a single APAP molecule and a substrate. We found that an increase in the association energy is related to an increase in the effectiveness of the substrate for enhancing the nucleation rate. We next developed a method based on molecular dynamics (MD) simulations of the interaction between the different crystal faces of APAP and the substrates. The method predicted the epitaxial growth of the crystal face (001)_APAP on top of the selected substrates based on strong hydrogen bond interactions with the substrates. The growth of the crystal face (001)_APAP was confirmed by SCXRD