Prediction of co-amorphous formation using non-bonded interaction energy: Molecular dynamic simulation and experimental validation

Co-amorphous (CA) formulation is a promising strategy to improve the solubility of poorly water-soluble drugs, however, effective prediction of a CA system is a challenge. In this study, a modified non-bonded interaction energy (Δ E non-bonded ) model was developed based on 105 solvent-based cases of 13 drugs chosen from the literature to predict CA formation by solvent-based methods using molecular dynamic simulation. With the cut-off value of −3500 kJ·mol −1 , the model hit 5 gefitinib CAs and 4 erlotinib CAs, validating its feasibility. The quadratic relationship between co-former proportion ( x co-former ) and Δ E non-bonded was analyzed using polynomial regression, indicating the x co-former is most likely to render CA when Δ E non-bonded reaches its extreme value. Hydrogen bonds between the NH group of active pharmaceutical ingredient and sulfonamide group of co-former were confirmed experimentally and computationally. Typical CA samples showed remarkable improved solubility (12.1 and 9.3 times) in PBS solution and good physical stability under room conditions.