Direct control of nucleation using heterosurfaces in a crystallization process is difficult to achieve due to the lack of fundamental mechanistic understanding on how these heterosurfaces participate in the process. Here, we aimed to evaluate and to expand the fundamental understanding of how biocompatible crystalline heterosurfaces can be utilized in order to maximize the nucleation rates of the model API acetaminophen (APAP). Five crystalline heterosurfaces, namely µ-D-galactose (DGAL), b-D-mannitol (b-DMAN), µ-D-mannitol (µ-DMAN), α-lactose monohydrate (LMH), and xylitol (XYL), all with a high density of hydroxyl groups per molecule, were evaluated. The nucleation rates of acetaminophen were measured using high-throughput in situ microscopy on a large number of crystallizations in the presence of selected crystalline substrates. We found that XYL enables particularly rapid crystallization. The comparable size match between APAP and XYL, leading to the high interaction energies supported by DFT calculations, could explain this observation. Furthermore, the effect of different polymorphs of the same substrate in altering the nucleation rates was minimum, supported by the results obtained with the polymorphs of DMAN. The effect of surface changes of LMH in ethanol was manifested by splitting the nucleation time scales of APAP, in the presence of this substrate. Additionally, substrate crystal faces where APAP crystals were bound were identified by single crystal X-ray diffraction and found to be rich in potential interacting sites. These results suggest that when functional organic substrates belonging to low symmetry groups are utilized in crystallization processes, the crystallization outcome is directly affected by the intermolecular interactions between the substrate and the overlayer and that the effect of lattice match is negligible.

Direct control of acetaminophen nucleation via functional, biocompatible crystalline substrates

254th National Meeting (2017)

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