Prediction of Solubility Parameters and Miscibility of Pharmaceutical Compounds by Molecular Dynamics Simulations

Abstract

The objectives of this study were (i) to develop a computational model based on molecular dynamics technique to predict the miscibility of indomethacin in carriers (polyethylene oxide, glucose, and sucrose) and (ii) to experimentally verify the in silico predictions by characterizing the drug-carrier mixtures using thermoanalytical techniques. Molecular dynamics (MD) simulations were performed using the COMPASS force field, and the cohesive energy density and the solubility parameters were determined for the model compounds. The magnitude of difference in the solubility parameters of drug and carrier is indicative of their miscibility. The MD simulations predicted indomethacin to be miscible with polyethylene oxide and to be borderline miscible with sucrose and immiscible with glucose. The solubility parameter values obtained using the MD simulations values were in reasonable agreement with those calculated using group contribution methods. Differential scanning calorimetry showed melting point depression of polyethylene oxide with increasing levels of indomethacin accompanied by peak broadening, confirming miscibility. In contrast, thermal analysis of blends of indomethacin with sucrose and glucose verified general immiscibility. The findings demonstrate that molecular modeling is a powerful technique for determining the solubility parameters and predicting miscibility of pharmaceutical compounds.

Scale-Dependent Miscibility of Polylactide and Polyhydroxybutyrate: Molecular Dynamics Simulations

“…Therefore, using atomistic simulations to evaluate miscibility and the dominant physical mechanisms has attracted a continuing attention of researchers. [32][33][34][35][36][37][38][39][40][41][42][43] MD simulations have been used to study the glass transition to predict miscibility of blended polymers. 33,[35][36][37] It has been established that interchain pair correlation functions may reflect structural properties of samples which can directly be related to miscibility.…”

Molecular Modeling as a Predictive Tool for the Development of Solid Dispersions

“…Thermal analysis has been used as a valuable tool to predict drug-polymer miscibility 19,[32][33][34] .…”

“…dissolution of the molecules from the crystal surface) 13 or to identify drug-polymer miscibility in solid dispersions [14][15][16][17][18] . Recently, we 19 reported the use of quantum mechanical (QM) calculations with commercially available software (Gaussian 09) to characterise possible drug/polymer interactions. Our calculations indicated the existence of hydrogen bonding between the amine group of the drug molecule and the carboxyl groups of the polymer among different drug/polymer formulations, which was subsequently, confirmed by NMR and X-ray photoelectron spectroscopy (XPS) studies.…”

Binding affinity between small molecules in solvent and polymer film using molecular dynamics simulations

“…With an appropriate interaction potential, MD simulations can predict many thermodynamics and transport properties of small molecules in a polymeric film such as the solubility parameter [13][14][15], the partition coefficient [16,17] and the diffusion coefficient [18][19][20]. In MD simulations, the prediction of binding affinity between two components is characterized through the solubility parameter ı.…”