Background/Objectives: This study aimed to establish a predictive model for critical quality attributes (CQAs) related to tablet integrity, including tablet breaking force (TBF), friability, and capping occurrence, using machine learning-based models and nondestructive experimental data. Methods: The machine learning-based models were trained on data to predict the CQAs of metformin HCl (MF)-containing tablets using a commercial-scale wet granulation process, and five models were each compared for regression and classification. We identified eight input variables associated with the process and material parameters that control the tableting outcome using feature importance analysis. Results: Among the models, the Gaussian Process regression model provided the most successful results, with R2 values of 0.959 and 0.949 for TBF and friability, respectively. Capping occurrence was accurately predicted by all models, with the Boosted Trees model achieving a 97.80% accuracy. Feature importance analysis revealed that the compression force and magnesium stearate fraction were the most influential parameters in CQA prediction and are input variables that could be used in CQA prediction. Conclusions: These findings indicate that TBF, friability, and capping occurrence were successfully modeled using machine learning with a large dataset by constructing regression and classification models. Applying these models before tablet manufacturing can enhance product quality during wet granulation scale-up, particularly by preventing capping during the manufacturing process without damaging the tablets.
