Multimodal Nonlinear Optical Imaging for Sensitive Detection of Multiple Pharmaceutical Solid-State Forms and Surface...

Area of Science:

• Pharmaceutical Sciences
• Chemical Imaging
• Materials Science

Background:

• Controlling solid-state forms is crucial for drug efficacy and stability.
• Sensitive imaging techniques are needed to analyze drug surfaces at (sub)micron resolution.
• Nonlinear optical microscopy offers label-free chemical specificity.

Purpose of the Study:

• To combine coherent anti-Stokes Raman scattering (CARS) and sum-frequency generation (SFG) for multimodal imaging of drug solid-state forms.
• To compare hyperspectral and simultaneous narrowband CARS/SFG imaging approaches.
• To investigate indomethacin crystallization on tablet surfaces under varying humidity conditions.

Main Methods:

• Coherent anti-Stokes Raman scattering (CARS) and sum-frequency generation (SFG) imaging.
• Hyperspectral CARS with principal component analysis (PCA) and SFG imaging.
• Simultaneous narrowband CARS and SFG imaging.
• Analysis of indomethacin crystallization under controlled humidity (30 °C/23% RH and 30 °C/75% RH).

Main Results:

• Distinguished three solid-state forms of indomethacin (gamma, alpha, amorphous) using both imaging approaches.
• Identified early-stage surface crystallization of indomethacin on tablets.
• Observed humidity-dependent crystallization: gamma form at low humidity, alpha form at high humidity.
• Demonstrated (sub)micron resolution imaging capability.

Conclusions:

• Multimodal nonlinear imaging (CARS/SFG) is a sensitive, specific, and rapid technique for analyzing solid-state forms in pharmaceuticals.
• The developed methods enable understanding and control of surface solid-state transformations.
• This approach is versatile for complex pharmaceutical samples and processes.