Due to the inevitable presence of heterosurfaces and favorable energetics, most crystallizations are initiated by heterogeneous nucleation. However, the fundamental mechanistic understanding of heterogeneous nucleation is still deficient which hinders the design and use of heterosurfaces for direct control of crystallization. On the other hand, the use of functional, organic molecular, crystalline substrates is limited due to their inherently complex surfaces. In this study, we investigated and optimized nucleation of selected active pharmaceutical ingredients (APIs) using biocompatible, functional crystalline heterosurfaces. The selection criteria for the substrates were based on the compatible interacting functional groups between the substrate surface and the API of interest. Furthermore, we explored the possibility of polymorphic selection of the APIs with a rational selection of the substrates. The effectiveness of different substrates towards the enhancement of the API nucleation was measured using high-throughput <i>in situ</i> microscopy on a large number of crystallizations. Additionally, single crystal X-ray diffraction studies were conducted to identify the substrate crystal faces where API crystals were bound. The identified substrate faces were rich with possible interacting groups suggesting 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 newly forming crystals. Our results indicate ways for fast and efficient selection of crystalline heterosurfaces for optimal nucleation of a given compound. Considering that, the main input for the selection is the compatible interacting sites on the heterosurface, we expect our results to be applicable to a wide range of crystallization processes.

Design of crystalline heterosurfaces for direct nucleation of active pharmaceutical ingredients

254th National Meeting (2017)

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