Decoding Formulation Complexity: Comparative Performance of Statistical, Machine Learning, and Artificial Intelligence Models in Intelligent Nano Depot (iNDEP) Design.

Artificial intelligence (AI) and machine learning (ML) are increasingly explored to improve predictive modelling and optimization in pharmaceutical formulation development. This study compared predictive performance of conventional statistical approaches and AI/ML-based models using an experimentally generated dataset from PLGA-mPEG-based Intelligent Nano Depot (iNDEP), smart depot forming long-acting injectable system for sustained co-delivery of Memantine hydrochloride (MH) and Galantamine hydrobromide (GH). Central Composite Design (CCD) dataset of 17 experimental formulations were employed to develop predictive models. The % cumulative drug release (CDR), implant formation time and particle size were measured to determine effects of PLGA-mPEG, Span 80 and Tween 80. Design of Experiments (DoE), SPSS-based Multiple Linear Regression (MLR), Artificial Neural Networks (ANN) and ML workflows in Orange Data Mining and KNIME Analytics Platform were used to produce predictive models. Root mean squared error (RMSE), mean squared error (MSE), and coefficient of determination (R