Control of Heterogeneous Nucleation via Rationally Designed Biocompatible Polymer Surfaces with Nanoscale Features

Direct control of nucleation in a crystallization process is difficult to achieve but offers many potential benefits to the food, chemicals, and pharmaceutical industries. We demonstrate a rational approach for designing and fabricating biocompatible polymer films that can drastically enhance nucleation rates and enable polymorph selection of small-molecule compounds. The core design philosophy was to calculate angles between major crystal faces and determine suitable substrate geometry to use for enhancing heterogeneous nucleation. Aspirin and indomethacin were used as model compounds; poly(vinyl alcohol) (PVA) with no additional chemical modification was made into films and imprinted with nanoscale features. Nucleation induction time experiments showed that using PVA films significantly reduced the nucleation induction time at a fixed supersaturation due to favorable chemical interactions and could be further reduced when the angles of the nano-indentations on the substrate matched the angles between different crystalline faces. X-ray diffraction (XRD) was used to reveal the interactions between the model compounds and PVA to suggest possible molecular packing in the indentations. Induction time and XRD results demonstrated validity of the rational design approach based on angle-directed nucleation. Finally, polymorph selection toward gamma-indomethacin with PVA substrates showed that it is possible to control polymorph composition of the final crystalline product by kinetically controlling the nucleation process. For the aspirin system, the 85 degrees angle led to the highest rate of nucleation; for the polymorphic indomethacin system, XRPD results showed that the gamma form preferentially formed on the PVA films with 65 degrees and 80 degrees angles leading to the largest reduction in nucleation induction time.