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Second Harmonic Generation Guided Raman Spectroscopy for Sensitive Detection of Polymorph Transitions.
Azhad U Chowdhury1, Dong Hye Ye2, Zhengtian Song1
1Department of Chemistry, Purdue University , 560 Oval Drive, West Lafayette, Indiana 47907, United States.
Analytical Chemistry
|May 9, 2017
Summary
This study integrates second harmonic generation (SHG) with Raman spectroscopy for pharmaceutical analysis. Automated SHG microscopy rapidly and accurately identifies crystal forms in clopidogrel bisulfate particles.
Area of Science:
- Analytical Chemistry
- Materials Science
- Pharmaceutical Science
Background:
- Pharmaceutical formulations require precise control over crystal forms for optimal bioavailability and efficacy.
- Distinguishing between different polymorphic forms of active pharmaceutical ingredients (APIs) is critical during drug development and manufacturing.
- Current analytical methods for crystal form analysis can be time-consuming or lack per-particle resolution.
Purpose of the Study:
- To develop and validate a rapid, automated method for discriminating between crystal forms of pharmaceutical materials using second harmonic generation (SHG) microscopy.
- To integrate SHG with Raman spectroscopy for comprehensive analysis of particulate pharmaceutical formulations.
- To assess the potential of SHG microscopy for real-time, at-line monitoring during pharmaceutical production.
Main Methods:
- Preparation of clopidogrel bisulfate in two distinct crystal forms (Form I and Form II).
- Automated particle identification using bright-field imaging.
- Classification of crystal forms using quantitative SHG microscopy.
- Complementary analysis using Raman spectroscopy and synchrotron X-ray diffraction (XRD).
Main Results:
- SHG microscopy achieved per-particle classification of crystal forms with 99.95% confidence in approximately 10 ms per particle.
- SHG classifications were in excellent agreement with complementary Raman and synchrotron XRD measurements.
- The developed method demonstrated limits of detection in the parts-per-million (ppm) regime.
Conclusions:
- Quantitative SHG microscopy offers a rapid and highly accurate method for crystal form analysis of pharmaceutical particles.
- The integration of SHG and Raman spectroscopy provides a powerful tool for comprehensive pharmaceutical material characterization.
- At-line monitoring using SHG holds promise for real-time process control in pharmaceutical manufacturing to favor desired polymorphs.
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