Transformation and Growth of Polymorphic Nuclei through Evaporative Deposition of Thin Films John D. Yeager,* ,† Kyle J. Ramos, † Nathan H. Mack, ‡ Hsing-Lin Wang, ‡ and Daniel E. Hooks † † Shock and Detonation Physics, Los Alamos National Laboratory, Los Alamos, New Mexico 87545, United States ‡ Physical Chemistry and Applied Spectroscopy, Los Alamos National Laboratory, Los Alamos, New Mexico 87545, United States * S Supporting Information ABSTRACT: 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. 1. INTRODUCTION Polymorph screening and selection is of great importance to the pharmaceutical industry. The crystal structure of a drug can affect the ease or quality of manufacturability as well as the medicinal properties. 1 Density, optical behavior, dissolution rate, and compaction are all examples of properties that vary by polymorph for many organic molecular crystals. Occasionally unexpected and harmful consequences result from previously undiscovered polymorphism. Perhaps the most well-known recent case was that of Ritonavir, in which a previously unknown polymorph with poor oral dissolution was accidentally manufactured and distributed and eventually resulted in a complete market withdrawal. 2 A comprehensive screening procedure could have detected the existence of this new polymorph, and later screening studies have shown a further three potential phases for this drug. 3 There is no current standard screening method, but most organizations follow similar procedures and solvent-based techniques are usually desirable. 2 Solvent-based screening approaches rely on sampling a diverse set of crystallization conditions by varying parameters such as strength of solvent-solute interactions, solubilities, and kinetics to increase the likelihood of observing different polymorphic forms. The probability that a particular form will appear is a function of free energy and the kinetic rate associated with crystal formation. 4 Less stable polymorphs can nucleate in solution as a result of higher nucleation rates. The persistence of the less stable forms during subsequent growth is determined by several factors though transformation to the stable form usually occurs over time. A solvent-mediated phase transformation can accelerate the process as solubility becomes size dependent: the metastable phase dissolves while the stable phase grows in its place in order to minimize the surface area and volume contribution to free energy. 5 This complex crystallization process, involving nucleation followed by growth and/or transformation, and metastable phases can make it difficult to interpret screening results and isolate less stable polymorphic forms. 6 Investigations of polymorph crystallization have utilized methods ranging from microanalytic techniques to sophisti- cated in situ techniques. 1 One common method for studying metastable forms involves melting a starting powder to an amorphous form, then combining spectroscopy with micros- copy and thermal analysis to observe and characterize polymorphic nuclei (e.g., Wu and Yu 7 ). However, solution- based techniques often have more applicability to pharmaceut- ical processes (i.e., wet formulation) and allow for a broad study of liquid-drug interactions. 6 In this work we study polymorphic nuclei through evaporative thin film deposition from solution. The evaporation of the solution takes place at room temperature in one to three seconds, rapid enough that the resulting solid film is in a Received: July 31, 2012 Revised: September 14, 2012 Published: September 26, 2012 Article pubs.acs.org/crystal © 2012 American Chemical Society 5513 dx.doi.org/10.1021/cg301090t | Cryst. Growth Des. 2012, 12, 5513-5520