Even trace crystallinity can profoundly affect the physical behavior of materials ranging from pharmaceutical ingredients to confectionaries. However, detection of low levels of crystallinity for small organic molecules like active pharmaceutical ingredients is notoriously challenging with existing benchtop instruments. In this project supported by the Chemical Measurement and Imaging Program of the Division of Chemistry, Professor Garth Simpson, his research group at Purdue University, and their industrial partner Merck & Co., Inc., will develop a new approach for crystal detection and quantification, based on nonlinear optical light-matter interaction. In sufficiently intense optical fields such as those arising in the focus of a femtosecond pulsed laser, normally weak interactions that scale nonlinearly with the intensity become significant. These new effects provide contrast in microscopy that is highly selective for crystals of small chiral molecules.
Quantitative second harmonic generation (SHG) microscopy instrumentation incorporating real-time data processing will be developed and applied for characterizing trace crystallinity at parts-per-million (ppm) levels, representing a 10,000-fold reduction in the lower limits of detection relative to existing common benchtop methods. Independent confirmation of trace crystal detection and percent crystallinity determination will be performed using a one-of-a-kind instrument integrating SHG microscopy and synchrotron X-ray diffraction. Initial applications will target analysis of amorphous formulations through collaborations between Purdue investigators and researchers at Merck. Partnering with Merck will help span the"valley of death" - obstacles that prevent drug discoveries transition to new drugs - to align fundamental discoveries on the nonlinear optics of chiral systems with the realities of private sector applications. If successful, the development of reliable benchtop tools for trace crystal detection could directly impact the design and quality control of drug formulations and potentially inform analyses of a significantly broader scope of biological materials.
