ABSTRACT The desired phase of a drug crystal at the interface between liquid–solid (or liquid–‐liquid) is commenced and governed by directed heterogeneous nucleation followed by the crystal growth process, influencing the properties, and applications, altering thermodynamics and kinetics of output crystals. The nucleation and crystal growth events of the highly polymorphic drug tolbutamide (TB) were investigated using a set of 10 different thiol‐based self‐assembled monolayers (SAMs) as heterogeneous functional surfaces. Common functional groups like ‐COOH, ‐OH, pyridine, benzimidazole, ‐CH 3 , and fluorine were presented on the SAM surface to control the crystallization process of TB. TB commonly crystallizes concomitantly in the slow evaporization of solvents method. Whereas, controlled nucleation of the stable polymorph II and two metastable polymorphs, that is, IV and V, were achieved on the designed functional surfaces. The SAM templates and output crystals were characterized with x‐ray diffraction, thermal analysis, microscopic imaging, and Raman spectroscopy. Whereas, Density Functional Theory (DFT) analysis was accomplished to apprehend the conformational barriers amongst the TB polymorphs to draw a rationale on the concomitant landscape of TB polymorphs. The BFDH morphology prediction and Hirshfeld surface analysis were performed to determine the possible interactions responsible for the controlled nucleation.
Goswami et al. (Fri,) studied this question.