Rapid Discrimination of Polymorphic Crystal Forms by Nonlinear Optical Stokes Ellipsometric Microscopy

Area of Science:

• Crystallography
• Materials Science
• Analytical Chemistry

Background:

• Polymorphism in active pharmaceutical ingredients (APIs) significantly impacts drug properties and efficacy.
• Rapid and accurate identification of solid-state forms is crucial during API development.
• Existing methods for polymorph screening can be time-consuming and resource-intensive.

Purpose of the Study:

• To demonstrate the efficacy of nonlinear optical Stokes ellipsometric (NOSE) microscopy for rapid discrimination of d-mannitol polymorphic forms.
• To establish a high-throughput screening method for solid-state characterization.
• To address bottlenecks in polymorph discovery during early-stage API development.

Main Methods:

• Utilized fast (8 MHz) polarization-modulated beam-scanning microscopy.
• Employed a novel iterative, nonlinear least-squares fitting algorithm.
• Applied standard statistical tests and two-class linear discriminant analysis to recovered probability density functions.

Main Results:

• Achieved discrimination between orthorhombic and monoclinic crystal structures of d-mannitol.
• Demonstrated rapid data acquisition times of less than 7 seconds per field of view.
• Obtained a high signal-to-noise ratio (SNR) of approximately 300.
• Attained discrimination within a 99.99% confidence interval.

Conclusions:

• NOSE microscopy offers a rapid and effective method for distinguishing d-mannitol polymorphs.
• The developed technique significantly enhances the speed of solid form screening.
• This advancement is valuable for high-throughput polymorph discovery in pharmaceutical development.