Basic Information
Abstract Number: 160-6    
Author Name: Garth Simpson Affiliation: Purdue University
Session Title: High-Throughput Chemical Analysis
Event Type: Oral
Event Title: Nucleation and Crystallization Kinetics in API Powders Probed by Second Order Nonlinear Optical Imaging of Chiral Crystals (SONICC)
Presider(s): Lynch, Garry J Start Time: 02:55 PM ( Slot # 7 )
Date: Sunday, March 11th, 2012 Location: 310B
Keywords: High Throughput Chemical Analysis, Materials Characterization, Microscopy, Particle Size and Distribution

Abstract Content
Second order non-linear optical imaging of chiral crystals (SONICC) is investigated as a rapid, selective, and ultra-sensitive probe for characterizing crystallinitiy in powdered preparations, including those of active pharmaceutical ingredients (API). Crystallization behaviors in powders can differ dramatically from those same properties measured in homogeneous bulk material and can be challenging to accurately measure. Nucleation kinetics measurements are particularly problematic using established methods, since they require reasonably high spatially resolution and crystal-specificity for reliable quantification. Second harmonic generation (SHG), or the frequency doubling of light, is symmetry forbidden in amorphous media, but allowed for the overwhelming majority of crystals with a chiral unit cell. Consequently, SONICC provides excellent selectivity for trace crystallinity of APIs. Furthermore, only the unscattered light contributes to the signals detected by SHG, allowing reliable measurements even in highly turbid media. Studies with model compounds (griseofulvin and chlorpropamide) demonstrate detection limits of SONICC for crystallinity better than 1 part in 100 billion by volume, corresponding to a ~8 order of magnitude improvement in % crystallinity compared to existing commonly used conventional methods (e.g., x-ray powder diffraction). The absence of a background response from disordered media allows the development of simple image analysis algorithms for automated quantification of nucleation rates, crystal growth rates, and activation energies for nucleation from a single set of measurements. Studies with powdered samples demonstrate the ability to easily quantify the residual 0.05% crystallinity remaining after exhaustive cryo-milling (S/N >1000) and obtain nucleation kinetics in powders with time-resolution per frame on the order of seconds.