Quantitative Analysis of Warfarin Tablets Containing Salt-Form Impurities Using Transmission Raman Spectroscopy

Significance of the Topic

Content uniformity and polymorph quantification are essential for ensuring consistent dosage and bioavailability in oral dosage forms
Transmission Raman spectroscopy offers a noninvasive bulk measurement that preserves polymorph information lost in chromatography
Rapid analysis at low dose levels reduces waste and resource use in pharmaceutical quality control

Objectives and Study Overview

The study aimed to quantify two salt forms of Warfarin in intact tablets at 0.5 w w using TRS without sample preparation
A design of experiments was employed to cover formulation variations and establish calibration models
Validation involved production batches and placebo tablets to assess predictive performance

Applied Methodology

A centric cubic design generated 19 calibration blends with Warfarin sodium and clathrate ratios spanning the target range
Each blend yielded seven tablets scanned in triplicate for a total of 399 spectra
Spectral preprocessing included baseline correction normalization and derivative transformations
Chemometric partial least squares models were built over selected wavenumber regions to correlate spectral features with concentration

Used Instrumentation

An Agilent TRS100 system with beam enhancer for remitting surface reflections and an 830 nm 650 mW laser source
Beam enhancer tray assembly improved light penetration for transmission measurements

Main Results and Discussion

Spectral differences at 680 818 1030 1420 1460 and 1635 cm 1 distinguished the two salt forms at low concentrations
PLS models achieved R2 values above 0.99 with root mean square calibration error of approx 0.019 w w and external prediction error of 0.026 w w
Normalized errors correspond to 4 5 percent relative to nominal concentration demonstrating high accuracy

Benefits and Practical Applications

Method enables non destructive content uniformity testing at low dose levels without solvents or sample prep
Ability to quantify polymorph populations supports formulation screening stability studies and batch release testing
Automated analysis improves throughput and reduces operator dependency in QC environments

Future Trends and Opportunities

Extension to other low dose APIs exhibiting polymorphism and complex coatings
Integration with online manufacturing control for real time release testing
Exploration of advanced chemometrics and hardware for deeper penetration and enhanced sensitivity

Conclusion

Transmission Raman spectroscopy provides rapid accurate nondestructive quantification of Warfarin salt forms in intact tablets at 0.5 w w
High model robustness under formulation variability and production samples highlights its suitability for pharmaceutical QC

References

1. Griffen JA Owen AW Matousek P Quantifying low levels under 0.5 w w of warfarin sodium salts in oral solid dose forms using transmission Raman spectroscopy Journal of Pharmaceutical and Biomedical Analysis 2018 155 276 283
2. Matousek P Raman signal enhancement in deep spectroscopy of turbid media Applied Spectroscopy 2007 61 845 854