Molecular dynamics simulations for drug dosage form development: thermal and solubility characteristics for hot-melt extrusion

Properties of pharmaceutical drug polymer mixtures like miscibility, stability and drug release are determined by the interactions of active pharmaceutical ingredients (APIs) and excipients (e.g. plasticisers) with functional polymers. Molecular dynamics (MD) simulations (Materials Studio, COMPASS force field) are used to predict the principal behaviour of such drug products, especially miscibility and glass transition temperature (Tg). Different mixtures containing APIs (theophylline or ibuprofen (IBU)) and water-soluble (triethyl citrate, (TEC)) or water-insoluble plasticiser (acetyl tributyl citrate (ATBC) or dibutyl sebacate (DBS)) dissolved/dispersed in a cationic polymethacrylate (EUDRAGIT RS) were studied. Force field-based calculations of the cohesive energy densities of single constituents led to a qualitative approach according to Hanson describing the solid state of the mixture, while further calculations on the basis of the theory of free energy of mixing facilitated a semi-quantitative prediction. In the case of miscibility also calculation of Tg was possible via modelling specific volumes of amorphous cells at various temperatures. The simulated data correlated well with the experimental data obtained from differential scanning calorimetry (DSC) of drug products processed via hot-melt extrusion. Accordingly, the described method facilitates a good estimate of pharmaceutical polymer drug mixtures, thus decreasing product development time, as well as the consumption of active ingredients.