Abstract: Objectives: This study is aimed to explore the blending process of Dahuang soda tablets. These are composed of two active pharmaceutical ingredients (APIs, emodin and emodin methyl ether) and four kinds of excipients (sodium bicarbonate, starch, sucrose, and magnesium stearate). Also, the objective is to develop a more robust model to determine the blending end-point. Methods: Qualitative and quantitative methods based on near-infrared (NIR) spectroscopy were established to monitor the homogeneity of the powder during the blending process. A calibration set consisting of samples from 15 batches was used to develop two types of calibration models with the partial least squares regression (PLSR) method to explore the influence of density on the model robustness. The principal component analysis-moving block standard deviation (PCA-MBSD) method was used for the end-point determination of the blending with the process spectra. Results: The model with different densities showed better prediction performance and robustness than the model with fixed powder density. In addition, the blending end-points of APIs and excipients were inconsistent because of the differences in the physical properties and chemical contents among the materials of the design batches. For the complex systems of multi-components, using the PCA-MBSD method to determine the blending end-point of each component is difficult. In these conditions, a quantitative method is a more suitable alternative. Conclusions: Our results demonstrated that the effect of density plays an important role in improving the performance of the model, and a robust modeling method has been developed.

Key words: Process analytical technology; Blending process; Near-infrared spectroscopy; End-point determination

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