Investigators: B. Bilyeu and C. Stevens (Xavier), M. D. Ward (NYU)

Polymorphism, the ability of a material to adopt different crystal forms, is well documented for many types of materials, including ceramics, metals, and polymers. This peculiar property has emerged as especially important in organic crystals and specialty chemicals, particularly pharmaceuticals, for which the discovery and characterization of polymorphs is essential for evaluation of shelf stability and bioavailability of the final pharmaceutical product. , , , Although different polymorphic structures can sometimes be created during crystallization, transformations in the solid state can be equally important. During crystallization organic compounds frequently form metastable structures, which can transform to more thermodynamically stable phases over time, sometimes provoked by temperature, pressure, humidity, shearing and compressive forces, or contact with other components (fillers and excipients).

Ward’s experience in synthesis and characterization of organic solid-state chemistry and polymorphism will be combined with Bilyeu’s expertise in thermal analysis of phase transitions and rearrangements in polymers and Stevens’ experience in x-ray crystallography of biomedical organic and inorganic crystals to develop new methods for the kinetic analyses of solid state polymorphic transitions in organic materials, with an emphasis on the nanoscale. Ward has developed methods to control polymorphism and to create and stabilize specific forms during crystallization, as well as AFM methods for identifying crystal structures during crystal growth. Bilyeu has developed techniques to determine the kinetics of small and challenging metastable transitions in polymers and macromolecules by thermal (calorimetry) and mechanical methods. Stevens has extensive experience in determining crystal structure by x-ray crystallography in many organic and inorganic compounds, including pressure-dependent structures. The research team will explore transformation kinetics of transitions due to external factors, including those mentioned above. These studies will dovetail with the current interests of the team’s investigators and will reinforce connections with Xavier’s XU Pharmacy School, the NYU Dental School, and with biomedical and pharmaceutical industries. The contacts established by the Ward group with several pharmaceutical companies, which are abundant in the NYC metropolitan area, will provide a gateway for Xavier students to this important industrial sector during summer research experiences. Furthermore, it will provide access to new pharmaceutical compounds that have been approved or are in trials, given the students a glimpse of real-world materials.

This project will begin with screening and identification of polymorphic forms, to be followed by investigation of their formation under conditions relevant to processing and storage of actual products. The research team initially will investigate the structural and thermal properties of well characterized materials, including those investigated previously by the team, such as glycine, anthranilic acid, 5-methyl-2-[(2-nitrophyenyl)amino]-3-thiophenecarbonitrile (ROY, for red-orange-yellow), chlorpropamide, and caffeine. Then actual commercial products containing these compounds will be analyzed in bulk and at the nanometer scale regions, specifically to determine the spatial distribution of polymorphs (in mixtures or aggregates) and to elucidate phase transformations at very early stages (i.e. at the nanoscale) that are instigated by thermal jumps or pressure (Figure 5). The identity and spatial distribution of polymorphs will be determined with a combination of “AFM goniometry,” first reported by Ward, , and AFM lattice imaging.   Furthermore, Bilyeu and Ward will employ AFM-based nanoscale thermal analysis, which allows precise determination of phase transition temperatures with nanoscale lateral resolution (for example, with the Veeco Instruments Thermal Analysis module). The results from the AFM thermal analysis will be compared with those of the bulk pure forms by differential scanning calorimetry and/or thermomechanical analysis for identification, but the spatial resolution of the AFM method will permit examination of phase transitions initiated on different crystal faces and the influence of defects. Stevens will identify the structures of the bulk pure forms with X-ray crystallography so that bulk structure can be correlated with thermal analyses signatures. Once the protocols for determining the kinetics of phase transformations and the influence of external factors have been developed with the aforementioned materials, the team will expand the scope to other known materials, including newly released pharmaceutical materials and those under development.