Application of AI in Tablet Development: An Integrated Machine Learning Framework for Pre-Formulation Property Prediction

Background/Objectives: Tablet development requires simultaneous optimization of multiple quality attributes under limited experimental budgets, yet formulation–property relationships are highly nonlinear in mixture systems. To support pre-formulation decision-making prior to extensive tablet prototyping, this study proposes an AI framework that organizes formulation and process data together with raw-material property records into a reusable database, and enriches conventional composition/process features with physically motivated mixture descriptors derived from raw-material properties and formulation/process settings. Methods: Mixture-level scalar descriptors are constructed by composition-weighted aggregation of material properties, and particle size distribution (PSD) is incorporated via a compact set of summary statistics computed from composition-weighted mixture PSDs. Three feature sets are compared: (i) Materials + Processes (MP), (ii) MP with scalar Descriptors (MPD), and (iii) MPD with PSD summaries (MPDD). Five target properties are modeled: hardness, disintegration time, flow function, cohesion, and thickness. We train and evaluate Random Forest, Extra Trees Regressor, Lasso, Partial Least Squares, Support Vector Regression, and a multi-branch neural network that processes the three feature blocks separately and concatenates them for prediction. For interpolation assessment, repeated Train/Dev/Test splitting (5:3:2) across multiple random seeds is used, and the effect of feature augmentation is quantified by paired RMSE improvements with bootstrap confidence intervals and paired Wilcoxon signed-rank tests. To assess robustness under practical formulation updates, rolling-origin time-series splits are employed and Applicability Domain indicators are computed to characterize out-of-distribution coverage. Results: Across interpolation evaluations, mixture-descriptor augmentation (MPD/MPDD) improves hardness and disintegration time in most settings, whereas gains for flow function are smaller and cohesion/thickness show mixed effects under limited sample sizes. Conclusions: Under extrapolation-oriented evaluation, the descriptors can improve hardness but may degrade disintegration-time prediction under covariate shift, emphasizing the need for careful descriptor selection and dimensionality control when deploying pre-formulation predictors.