title: 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.
authors.affiliation: Department of Pharmaceutics, Philadelphia College of Pharmacy, University of the Sciences in Philadelphia, Philadelphia, Pennsylvania 19104, USA. jasmine.gupta@bms.com
authors.forename: Jasmine
authors.initials: J
authors.lastname: Gupta
authors.forename: Cletus
authors.initials: C
authors.lastname: Nunes
authors.forename: Shyam
authors.initials: S
authors.lastname: Vyas
authors.forename: Sriramakamal
authors.initials: S
authors.lastname: Jonnalagadda
mesh_terms: D019295:Computational Biology; D004337:Drug Carriers / Q000737:chemistry; D005947:Glucose / Q000737:chemistry; D007213:Indomethacin / Q000737:chemistry; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry; D012995:Solubility; D013395:Sucrose / Q000737:chemistry; D013696:Temperature; D013816:Thermodynamics
chemical_list: D004337:Drug Carriers; D004364:Pharmaceutical Preparations; D011092:Polyethylene Glycols; D013395:Sucrose; D005947:Glucose; D007213:Indomethacin