Elucidation of Molecular Interactions Between Drug–Polymer in Amorphous Solid Dispersion by a Computational Approach Using Molecular Dynamics Simulations

Diah Lia Aulifa,1 Adnan Aly Al Shofwan,2 Sandra Megantara,1 Taufik Muhammad Fakih,3 Arif Budiman2 1Department of Pharmaceutical Analysis and Medicinal Chemistry, Faculty of Pharmacy, Universitas Padjadjaran, Sumedang, Indonesia; 2Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Universitas Padjadjaran, Sumedang, Indonesia; 3Department of Pharmacy, Faculty of Mathematics and Natural Sciences, Universitas Islam Bandung, Bandung, IndonesiaCorrespondence: Diah Lia Aulifa, Department of Pharmaceutical Analysis and Medicinal Chemistry, Faculty of Pharmacy, Universitas Padjadjaran, Jl. Raya Bandung-Sumedang Km. 21, Sumedang, 45363, Indonesia, Email diah.lia@unpad.ac.idIntroduction: Amorphous drug dispersion is frequently used to enhance the solubility and dissolution of poorly water-soluble drugs, thereby improving their oral bioavailability. The dispersion of these drugs into polymer matrix can inhibit their recrystallization. The inter-molecular interactions between drug and polymer plays a role in the improvement of the dissolution rate, solubility, and physical stability of drug.Aim: This study aims to investigate the formation and interactions of ritonavir (RTV)/poloxamer (PLX) amorphous formulation using a computational approach via molecular dynamics (MD) simulations, which mimicked solvent evaporation and melt-quenching method.Methods: TheRoot Mean Square Deviation (RMSD) value, Root Mean Square Fluctuation (RMSF), Radial Distribution Function (RDF), Radius of Gyration (Rg), Solvent Accessible Surface Area (SASA), and hydrogen bond interactions were analyzed to determine interaction mechanisms between RTV and PLX in amorphous solid dispersion.Results: The pi-alkyl bonds between RTV and PLX were formed after simulations of solvent evaporation, while the hydrogen bond interactions of RTV-PLX was observed during melt method simulations. These results indicate the successful formulation of amorphous solid dispersion (ASD) from RTV and PLX. The RMSD values obtained from the solvent evaporation, melt-cooling-A, melt-cooling-B, and melt-cooling-C methods were 3.33 Å, 1.97 Å, 1.30 Å, and 1.29 Å, respectively, while the average RMSF values were 2.65 Å, 1.04 Å, 1.05 Å, and 1.07 Å, respectively. This indicates that the suppression of translational motion of RTV from the melt method can be stronger than solvent evaporation caused by the intermolecular interactions of RTV-PLX.Conclusion: MD simulations helped in understanding the formation and interaction mechanisms of ASD formulations that were difficult to detect by experimental approaches.Keywords: amorphous solid dispersion, molecular interaction, molecular dynamics simulations, ritonavir, poloxamer