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

Abstract

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.

Self-Assembled Monolayers As a Tool to Investigate the Effect of Surface Chemistry on Protein Nucleation

“…The three selected chemistries guaranteed highly reproducible and stable surface functionalization, comparable wettability, and subnanometer roughness, as determined by AFM (Figure S1). Alternative surface chemistries, such as amino-terminated SAMs, were excluded because of the instability of surface chemistry over time. , Depending on the nature of the protein and its phase diagram, studying the action of surfaces on crystallization may be more or less challenging. Heterogeneous nucleation can only be studied when crystallization conditions fall in the metastable zone of the protein phase diagram.…”

“…In our recent publication, we investigated the action of self-assembled monolayers (SAMs) immobilized on glass on the crystallization of a model active pharmaceutical ingredient (API), i.e., aspirin . SAMs turned out to have a dramatic impact on the nucleation step, both in terms of nucleation kinetics and preferential orientation of crystal faces nucleated on the surface.…”

A Covalent Organic Framework Membrane with Homo Hierarchical Pores for Confined Reactive Crystallization

“…In principle, the thermodynamics and kinetics of crystal nucleation are determined by local supersaturation and the microstructure of the heterogeneous nucleation interface, which are not only affected by mixing efficiency but also closely related to interface engineering, especially the porous structure of the interface. − The well fabricated material interface presented ideal performance on the mass transfer control, supersaturation generation, and nucleation regulation for diverse crystallization processes. − Covalent organic frameworks (COFs) with nanoscale pores and ordered networks have become an attractive porous material. − The nanoscale regular pores of COFs could be comparable to the unit cells of many compounds and not only provide heterogeneous nucleation sites but also guide the orderly and rapid growth of the initial nucleus along the long axis. − In addition, nanoscale pores could promote the rapid aggregation of solute molecules to form critical nuclei through heterogeneous nucleation on the pore walls, while the larger microscale pores could provide more filled crystals as the heterogeneous nucleation interface to promote crystal growth. ,− The ordered networks in COFs can regulate the diffusion and nucleation process. As the crystallization process requires an extremely high reaction unit diffusion rate and precise nucleation control, how to construct a suitable reactive interface has become a core concern .…”

Role of Heteronucleants in Melt Crystallization of Crystalline Solid Dispersions

“…In contrast to melt crystallization, several strategies are reported to selectively crystallize the desired polymorph from solutions. ,, Without claiming to be exhaustive, some of these methods are supersaturation control (crash cooling, thermal cyclings, and solvent evaporation), seeding with desired polymorph, ultrasound-assisted crystallization, multicomponent crystallization, and heterogeneous nucleation. − In particular, heterogeneous nucleation, a method that induces crystallization through specific solute–substrate interactions employing a foreign surface, has been used to achieve enhanced control over the crystallized polymorph. , Some of the most promising heteronucleants are gels, self-assembled monolayers (SAMs), − crystalline substrates, and polymer surfaces. − Although heterogeneous nucleation using polymeric surfaces has been demonstrated to be helpful in providing kinetic access to novel crystalline forms in solution crystallization, ,− this approach is highly underexplored in combination with melt crystallization …”