Real-time monitoring of small changes in powder blends and ejected tablets in a low-dose formulation with 1 %w/w of active pharmaceutical ingredient using Raman and near-infrared spatially resolved spectroscopy within a tablet press.

This study used Raman and near-infrared (NIR) spectroscopy to monitor small real-time changes in powder blends and tablets in low-dose pharmaceutical formulations. The research aims to enhance process analytical technology (PAT) in pharmaceutical manufacturing, ensuring high-quality and uniform products with applications to produce drugs with narrow therapeutic indices (NTI). The study utilizes Raman and NIR spatially resolved spectroscopy (SRS) techniques to monitor a moderate cohesive material's active pharmaceutical ingredient (API) concentrations during manufacturing. The sampling locations were a bin blender for the batch blending procedure where the powder heterogeneity plays a significant role in product homogeneity, a feed frame of a tablet press where powder blend dynamics is critical to final product quality, and the outlet port of the tablet press where tablets immediately after ejection can be monitored in real-time. The study used semifine acetaminophen (APAP) as the API. Results indicated that Raman and NIR SRS could detect small API concentration changes as low as 0.50 %w/w, demonstrating their sensitivity and utility in real-time monitoring. The findings support the feasibility of these techniques in ensuring tight process control and highlight the performance of reducing waste and optimizing manufacturing processes in line with quality by design principles. The results highlight the importance of residence time distribution (RTD) in understanding the flow of the materials and powder behavior within the tablet press feed frame. RTD analyses showed that both Raman and NIR SRS techniques could effectively track concentration changes and ensure uniformity in the powder blends and tablets with signal-to-noise ratios higher than 3, demonstrating the sensitivity of the methods to small API changes. The %RSD during a steady state of 250 s (corresponding to 1.04 kg of material at 15 kg/h) for the step changes presented values of 6.74 % at 0.50 %w/w, 5.39 % at 1.00 %w/w, and 2.99 % at 1.50 %w/w for Raman predictions in powder blends within the feed frame and 15.46 % at 0.50 %w/w, 9.64 % at 1.00 %w/w, and 5.68 % at 1.50 %w/w for NIR SRS predictions of tablets ejected at the outlet port of the tablet press. In conclusion, this research demonstrates the potential of advanced spectroscopic techniques and data analysis in pharmaceutical manufacturing. By enabling precise real-time monitoring and control, these techniques contribute to higher-quality drug products, particularly NTI drugs, aligning with modern regulatory expectations and advancing pharmaceutical production technology.