Portable Raman Spectroscopy for the Study of Polymorphs and Monitoring Polymorphic Transitions

Significance of the Topic

Polymorphism affects the physical and chemical properties of materials while they retain the same composition. In pharmaceuticals, different crystal forms can alter solubility, stability, and bioavailability of active ingredients. Portable Raman spectroscopy provides a rapid, noninvasive method for distinguishing polymorphs and monitoring solid-state transitions in real time, supporting quality control and process optimization.

Objectives and Study Overview

This work aims to demonstrate the capability of portable Raman spectrometers for identifying polymorphs and tracking polymorphic transitions. Case studies include calcium carbonate (aragonite versus calcite), citric acid (monohydrate versus anhydrous), and dextrose (anhydrous versus monohydrate). A detailed investigation focuses on the temperature-driven conversion of citric acid monohydrate to the anhydrous form using continuous spectral monitoring.

Methodology and Instrumentation

Ultrabroadband portable Raman systems equipped with TE-cooled CCD detectors and CleanLaze 785 nm excitation lasers were used for in situ analysis. Key features include:

• Spectral range from approximately 65 to 3350 cm-1
• Integration times of 15–30 seconds with 300 mW laser power
• Fiber-optic probes with immersion shafts for controlled sampling
• BWSP-21pt11 software for continuous data acquisition, peak trending, and multivariate analysis (PCA)

Main Results and Discussion

Distinct Raman fingerprints were observed for all polymorphic pairs: aragonite and calcite calcium carbonate, citric acid forms, and dextrose variants. During heating of citric acid monohydrate to 80 °C:

• An evolving decrease of the 1108 cm-1 peak (monohydrate) and concurrent increase of the 1146 cm-1 peak (anhydrous) were tracked in real time.
• Additional marker peaks such as 442, 820, and 1260 cm-1 (monohydrate) and 1635, 2932, and 2982 cm-1 (anhydrous) confirmed the phase transition.
• Principal Component Analysis over the full spectral range captured 90% of variance in PC-1 scores, mirroring single-peak trends and reflecting systematic spectral changes during the transition.

Benefits and Practical Applications

Portable Raman spectroscopy offers:

• Rapid, nondestructive identification of polymorphic forms without sample preparation
• Real-time process monitoring for crystallization, drying, and phase transitions
• Compact and easy-to-deploy solutions for process development, scale-up, and quality control
• Compatibility with chemometric tools for automated analysis and decision support

Future Trends and Potential Uses

• Integration with advanced chemometrics and machine learning for automated polymorph recognition
• Development of miniaturized Raman devices for inline monitoring in pharmaceutical production lines
• Expansion into remote and hazardous environments using wireless or autonomous probes
• Enhanced spectral libraries and cloud-based analytics for cross-laboratory standardization

Conclusion

This study highlights the effectiveness of portable Raman spectroscopy in identifying and monitoring polymorphic forms. The ability to perform real-time, noninvasive measurements supports pharmaceutical development, quality assurance, and process analytical technology. Multivariate analysis further enhances detection sensitivity and robustness in complex phase-transition studies.

Reference

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