ARTICLE pubs.acs.org/ac
Single Particle Nonlinear Optical Imaging of Trace Crystallinity in an Organic Powder D. Wanapun,† U.S. Kestur,‡ L. S. Taylor,*,‡ and G. J Simpson*,† † ‡
Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana 47907, United States Department of Industrial and Physical Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana 47907, United States
bS Supporting Information ABSTRACT: Microscopic characterization of crystallinity in powders can reveal information lost in ensemble-averaged measurements. Nonlinear optical imaging based on second harmonic generation (SHG) provides rapid and highly selective detection of individual chiral microcrystals, enabling insights into the fundamental mechanism of action for the observed crystallinity loss of an organic powder induced by mechanical grinding. Using griseofulvin as the model compound, the results from second order nonlinear optical imaging of chiral crystals (SONICC) compared favorably with those of powder X-ray diffraction (PXRD) over the linear dynamic range of the PXRD measurements. However, the SHG measurements demonstrated three decade improvements in linear dynamic range. The detection limit of SHG was estimated to be 4 ppm crystallinity in the powder. The rate of crystallinity loss induced by milling followed a first order process with a half-life of 15 ( 1 min. Recrystallization of cryomilled powder is ∼40 times faster than that prepared by melt-quenched powder, suggesting that the disordered state obtained by exhaustive cryomilling appears to contain ordered domains that are larger than the critical nucleation size, but below the detection limit of SONICC. The presence of such domains provides a barrier-less nucleation source resulting in rapid crystallization, the kinetics of which depends only on crystal growth.
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he solid state form of an organic powder dramatically influences both its chemical and physical properties. For example, the bioavailability of an active pharmaceutical ingredient can change substantially depending on the solid state form, with even trace residual crystallinity significantly impacting shelf life. Improved fundamental understanding of the solid state phase heterogeneity is currently limited in large part by major challenges in accurately quantifying trace crystallinity (
