Role of Self-Assembled Surface Functionalization on Nucleation Kinetics and Oriented Crystallization of a Small-Molecule Drug: Batch and Thin-Film Growth of Aspirin as a Case Study.

The present paper assesses the heterogeneous nucleation of a small-molecule drug and its relationship with the surface chemistry of engineered heteronucleants. The nucleation of aspirin (ASA) was tuned by different functional groups exposed by self-assembled monolayers (SAMs) immobilized on glass surfaces. Smooth topographies and defect-free surface modification allowed the deconvolution of chemical and topographical effects on nucleation. The nucleation induction time of ASA in batch crystallization was mostly enhanced by methacrylate and amino groups, whereas it was repressed by thiol groups. In this perspective, we also present a novel strategy for the evaluation of surface-drug interactions by confining drug crystallization to thin films and studying the preferential growth of crystal planes on different surfaces. Crystallization by spin coating improved the study of oriented crystallization, enabling reproducible sample preparation, minimal amounts of drug required, and short processing time. Overall, the acid surface tension of SAMs dictated the nucleation kinetics and the extent of relative growth of the ASA crystal planes. Moreover, the face-selective action of monolayers was investigated by force spectroscopy and attributed to the preferential interaction of exposed groups with the (100) crystal plane of ASA.