Abstract
The use of nonlinear optical Stokes ellipsometric (NOSE) microscopy for rapid discrimination of two polymorphic forms of the small molecule D-mannitol is presented. Fast (8 MHz) polarization modulated beam-scanning microscopy and a recently developed iterative, nonlinear least-squares fitting algorithm were combined to allow discrimination of orthorhombic and monoclinic crystal structures of D-mannitol with data acquisition times of <7 s per field of view with a signal-to-noise ratio (SNR) of similar to 300. Discrimination between polymorphic forms within the 99.99% confidence interval was achieved by standard statistical tests of the recovered probability density functions for the measured observables following two class linear discriminant analysis. These measurements target bottlenecks in small-volume, high-throughput solid form screening experiments for polymorph discovery in the development of emerging active pharmaceutical ingredients.