Evaluation of co-amorphous systems containing ritonavir and coformers: An experimental and molecular simulation study

This study investigates the role of saccharin (SAC) and nicotinamide (NIC) as co-formers in the formulation of ritonavir (RTV) using two different preparation methods: melt-cooling and solvent evaporation via experimental and computational study. Characterization of coamorphous RTV was evaluated by Powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC) and fourier transform infrared (FT-IR) spectroscopy measurement. Molecular dynamics (MD) simulations were conducted over a 500 ns timescale for both melt-cooling and solvent evaporation formulations. Structural analyses were performed using Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF), Radius of Gyration (Rg), and Solvent Accessible Surface Area (SASA) to assess stability and compactness. Radial Distribution Function (RDF) analysis was employed to determine molecular organization, while hydrogen bonding interactions were examined to evaluate the stabilizing role of each co-former. The amorphization of RTV and each coformer (SAC and NIC) was confirmed as a halo pattern in PXRD measurements and the absence of endothermic peak in the DSC curve. FT-IR spectroscopy revealed a hydrogen bond between the RTV and NIC. In MD simulations, RTV-NIC exhibited the most stable conformation in both preparation methods, with the lowest RMSD, Rg, and SASA values, signifying strong molecular packing and minimal solvent exposure. RTV-SAC displayed intermediate behavior, maintaining a balance between flexibility and stability with transient yet recurring hydrogen bonding interactions. RDF analysis confirmed that RTV-SAC and RTV-NIC formed more compact and stable molecular arrangements across both formulation methods. These findings suggest that co-former selection and preparation methods significantly impact the final stability of pharmaceutical formulations.