Transformation and growth of polymorphic nuclei through evaporative deposition of thin films

Rapidly dip-coating a silicon substrate in an acetaminophen solution creates a thin film of polymorphic nuclei, and the relative amounts of each polymorph vary with the type of solvent. Polarized light microscopy (PLM) revealed that all films were initially amorphous and gradually crystallized over time scales of minutes to hours. Fourier transform infrared spectroscopy (FTIR) was used to identify the polymorphic form during crystallization and weeks after apparent stabilization of growth. Crystallites that initially nucleated from the amorphous films were found to be the metastable orthorhombic form. Over time, the orthorhombic crystallites stopped growing and the remaining amorphous regions transformed to the stable monoclinic form. The choice of solvent determined how fast the orthorhombic crystallites grew and thus controlled the polymorphic character of the film. For example, dip-coating from an ethanol solution produced a largely orthorhombic film, while water yielded a film with mixed character. Kinetic arguments are made to discuss these results in terms of relative nucleation rates, supersaturation, and evaporation rate of the solvent. We demonstrate that PLM and FTIR are suitable tools for exploring phase space with these thin films. This methodology might be applied broadly to polymorph screening and selection in evaluating pharmaceutical materials.