QTRam® for Content Uniformity Analysis of Low-Dose Pharmaceutical Tablets

Significance of the Topic

Orally administered compressed tablets must comply with stringent content uniformity requirements, especially for low-dose active pharmaceutical ingredients (APIs). Conventional methods such as titration or HPLC are destructive, time-consuming, and generate chemical waste. Transmission Raman Spectroscopy (TRS) enables nondestructive, rapid bulk analysis, offering major advantages for at-line quality control and streamlined workflows.

Objectives and Overview of the Study

This study evaluates the performance of the QTRam® compact TRS analyzer for quantifying trace levels of acetaminophen (APAP) in a model tablet formulation. A hypothetical 0.5% APAP w/w tablet series was prepared across nine concentration levels to assess calibration accuracy, sensitivity, and precision in content uniformity testing.

Methodology

Nine powder blends containing APAP, mannitol, silicified microcrystalline cellulose (MCC), croscarmellose (CMC), and magnesium stearate were compressed into 300 mg tablets (10 mm diameter, 3 mm thickness). Transmission Raman spectra were acquired through a 4 mm aperture, averaging 10 scans of 3 s each. Chemometric modeling employed PLS1 regression with preprocessing: Savitzky–Golay first derivative, spectral range selection (200–1700 cm⁻¹), Standard Normal Variate normalization, and mean centering.

Instrumentation

• QTRam® Transmission Raman Spectrometer (model BWT-840000893, B&W Tek)
• BWAnalyst® software (21 CFR Part 11 compliant) for data acquisition
• BWIQ® chemometric software for PLS regression

Main Results and Discussion

Initial calibration across all nine blends achieved an RMSEC of 0.046% APAP w/w (4 latent variables). Restricting to blends ≤ 1.5% yielded RMSEC = 0.022% and RMSECV = 0.027%. Validation on 0.5% and 0% tablets produced an RMSEP of 0.023% with bias of 0.008%. The estimated LOD and LOQ were 0.074% and 0.23% APAP w/w, respectively. Precision, calculated from six replicate runs, was 0.016% APAP w/w, demonstrating robust quantification at low concentrations.

Benefits and Practical Applications of the Method

• Nondestructive measurement preserves sample integrity for further testing.
• Rapid data acquisition (≈30 s per spectrum) supports at-line deployment.
• No solvents or consumables reduce waste and operating costs.
• High sensitivity and accuracy facilitate compliance with regulatory standards (USP <905>).

Future Trends and Applications

Advances in TRS hardware and chemometric algorithms are expected to lower detection limits and enhance model robustness. Automated sample handling could enable high-throughput screening. Integration with complementary spectroscopic techniques (e.g., NIR) may broaden multicomponent analysis, further streamlining pharmaceutical quality control.

Conclusion

The QTRam TRS analyzer delivers fast, accurate, and nondestructive content uniformity testing for low-dose tablets. Its minimal sample preparation, strong chemometric performance, and at-line capability align with modern quality by design principles and regulatory requirements.