Differentiation of polymorphs using near infrared spectroscopy (NIRS)

Significance of Topic

Near infrared spectroscopy offers a rapid and nondestructive approach to distinguish crystalline forms of active pharmaceutical ingredients. Polymorphism can influence solubility, stability, and bioavailability of drugs. Identifying and controlling polymorphic forms during production, storage, and quality control is critical to meet regulatory standards and ensure therapeutic efficacy.

Objectives and Study Overview

This study aimed to demonstrate how near infrared spectroscopy differentiates between commercial sulfathiazole and its least stable polymorph form I. The goal was to develop a fast identification method that can be applied in incoming goods inspection, in-process monitoring, and final product verification, offering a secondary technique complementing X-ray diffraction.

Methodology and Instrumentation

The study synthesized sulfathiazole form I from the commercial material. Spectra were collected in stationary diffuse reflection mode over 400–2500 nm with 32 co-added scans per sample. Standard Normal Variate preprocessing minimized scatter effects. Correlation in wavelength space with a threshold of 0.9 was used to build a reference library. Internal cross-validation assessed classification reliability.
Used Instrumentation

• NIRS DS2500 Analyzer with Mini Sample Cup Holder and Iris module
• NIRS XDS SmartProbe Analyzer with 2 m fiber and interchangeable probe assembly
• Vision Pharma 4.1 chemometric software

Main Results and Discussion

The first overtone region of the N-H stretching vibration (1400–1720 nm) exhibited the greatest spectral differences between form I and the commercial polymorph. Form I displayed distinct absorbance features in this region, enabling clear differentiation. The developed library achieved accurate identification in cross-validation, and the method was successfully transferred to the SmartProbe setup for rapid raw material screening.

Benefits and Practical Applications

• Significant reduction in analysis time compared to X-ray diffraction
• Non-destructive testing suitable for in-line process monitoring
• Simple sample handling with disposable vials
• High-throughput screening of incoming materials and final products

Future Trends and Possibilities for Use

Advances in portable NIR instrumentation and probe technology will enable real-time monitoring of polymorphic transformations during crystallization. Integration with advanced chemometric models and machine learning could further improve specificity and automation. Expanded application to other antibiotics and complex formulations is anticipated.

Conclusion

Near infrared spectroscopy effectively discriminates sulfathiazole form I from the commercial polymorph by targeting N-H overtone vibrations. The method provides a fast, reliable secondary tool for polymorph identification in pharmaceutical quality control and process development.

Reference

• NIR Application Note NIR-37, Metrohm