Insights into pharmaceutical co-crystallization using coherent Raman microscopy

Area of Science:

• Pharmaceutical Sciences
• Chemical Engineering
• Materials Science

Background:

• Co-crystallization is crucial for formulating active pharmaceutical ingredients (APIs).
• Understanding co-crystallization behavior under various process conditions is essential for successful formulation.
• Established analytical methods may not fully capture the complex dynamics of co-crystallization.

Purpose of the Study:

• To investigate the application of coherent Raman microscopy techniques for studying co-crystallization.
• To compare narrowband coherent anti-Stokes Raman scattering (CARS) and hyperspectral stimulated Raman scattering (SRS) for co-crystallization analysis.
• To evaluate the ability of these techniques to provide qualitative and quantitative insights into the co-crystallization process.

Main Methods:

• Liquid-assisted ball milling was used to induce co-crystallization of indomethacin and nicotinamide.
• Narrowband CARS microscopy with univariate peak position analysis was employed.
• Hyperspectral SRS imaging combined with classical least squares multivariate analysis was utilized.
• Results were compared with conventional solid-state analysis methods.

Main Results:

• Narrowband CARS visualized co-crystal formation but faced challenges with component identification due to signal mixing.
• Hyperspectral SRS imaging provided confident separation of components, proving robust for qualitative and quantitative co-crystallization imaging.
• Coherent Raman imaging explained divergent endpoints from conventional methods and detected trace forms.
• The study demonstrated the influence of ethanol content on co-crystal formation reversal during milling.

Conclusions:

• Coherent Raman microscopy, particularly SRS, is a valuable tool for analyzing co-crystallization processes.
• These techniques offer enhanced insights into co-crystal formation, including the detection of trace components and process dynamics.
• The findings highlight the added value of coherent Raman microscopy for pharmaceutical formulation development.